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This article combines a brief introduction into a particular philosophical theory of "time" with a demonstration of how this theory has been implemented in a Literary Studies oriented Humanities Computing project. The aim of the project was to create a model of text-based time cognition and design customized markup and text analysis tools that help to understand ‘‘how time works’’: more precisely, how narratively organised and communicated information motivates readers to generate the mental image of a chronologically organized world. The approach presented is based on the unitary model of time originally proposed by McTaggart, who distinguished between two perspectives onto time, the so-called A- and B-series. The first step towards a functional Humanities Computing implementation of this theoretical approach was the development of TempusMarker—a software tool providing automatic and semi-automatic markup routines for the tagging of temporal expressions in natural language texts. In the second step we discuss the principals underlying TempusParser—an analytical tool that can reconstruct temporal order in events by way of an algorithm-driven process of analysis and recombination of textual segments during which the "time stamp" of each segment as indicated by the temporal tags is interpreted.
This paper provides an analysis of an alternative strategy to A´-movement in both German and Dutch where the extracted constituent is preceded by a preposition and a coreferential pronoun appears in the extraction site. The construction has properties of both binding and movement: Whereas reconstruction effects suggest movement out of the embedded clause, there is strong evidence that the operator constituent is linked to an A-position in the matrix clause; this paradox is resolved by assuming a Control-like approach that involves movement from the embedded clause into a theta-position in the matrix clause with subsequent short A´- movement. The coreferential pronoun is interpreted as a resumptive heading a Big-DP which hosts the antecedent in its specifier.
Fronting of an infinite VP across a finite main verb - akin to German "VP-topicalization" - can be found also in Czech and Polish. The paper discusses evidence from large corpora for this process and some of its properties, both syntactic and information-structural. Based on this case, criteria for more user-friedly searching and retrieval of corpus data in syntactic research are being developed.
This paper describes the creation and preparation of TUSNELDA, a collection of corpus data built for linguistic research. This collection contains a number of linguistically annotated corpora which differ in various aspects such as language, text sorts / data types, encoded annotation levels, and linguistic theories underlying the annotation. The paper focuses on this variation on the one hand and the way how these heterogeneous data are integrated into one resource on the other hand.
Face-to-face communication is multimodal. In unscripted spoken discourse we can observe the interaction of several “semiotic layers”, modalities of information such as syntax, discourse structure, gesture, and intonation. We explore the role of gesture and intonation in structuring and aligning information in spoken discourse through a study of the co-occurrence of pitch accents and gestural apices. Metaphorical spatialization through gesture also plays a role in conveying the contextual relationships between the speaker, the government and other external forces in a naturally-occurring political speech setting.
Elke Kasimir´s paper (in this volume) argues against employing the notion of Givenness in the explanation of accent assignment. I will claim that the arguments against Givenness put forward by Kasimir are inconclusive because they beg the question of the role of Givenness. It is concluded that, more generally, arguments against Givenness as a diagnostic for information structural partitions should not be accepted offhand, since the notion of Givenness of discourse referents is (a) theoretically simple, (b) readily observable and quantifiable, and (c) bears cognitive significance.
The semantics of ellipsis
(2005)
There are four phenomena that are particularly troublesome for theories of ellipsis: the existence of sloppy readings when the relevant pronouns cannot possibly be bound; an ellipsis being resolved in such a way that an ellipsis site in the antecedent is not understood in the way it was there; an ellipsis site drawing material from two or more separate antecedents; and ellipsis with no linguistic antecedent. These cases are accounted for by means of a new theory that involves copying syntactically incomplete antecedent material and an analysis of silent VPs and NPs that makes them into higher order definite descriptions that can be bound into.
This paper discusses the use of XSLT stylesheets as a filtering mechanism for refining the results of user queries on treebanks. The discussion is within the context of the TIGER treebank, the associated search engine and query language, but the general ideas can apply to any search engine for XML-encoded treebanks. It will be shown that important classes of linguistic phenomena can be accessed by applying relatively simple XSLT templates to the output of a query, effectively simulating the universal quantifier for a subset of the query language.
In order to investigate the empirical properties of focus, it is necessary to diagnose focus (or: “what is focused”) in particular linguistic examples. It is often taken for granted that the application of one single diagnostic tool, the so-called question-answer test, which roughly says that whatever a question asks for is focused in the answer, is a fool-proof test for focus. This paper investigates one example class where such uncritical belief in the question-answer test has led to the assumption of rather complex focus projection rules: in these examples, pitch accent placement has been claimed to depend on certain parts of the focused constituents being given or not. It is demonstrated that such focus projection rules are unnecessarily complex and in turn require the assumption of unnecessarily complicated meaning rules, not to speak of the difficulties to give a precise semantic/pragmatic definition of the allegedly involved givenness property. For the sake of the argument, an alternative analysis is put forward which relies solely on alternative sets following Mats Rooth´s work, and avoids any recourse to givenness. As it turns out, this alternative analysis is not only simpler but also makes in a critical case the better predictions.
This paper investigates the structural properties of morphosyntactically marked focus constructions, focussing on the often neglected non-focal sentence part in African tone languages. Based on new empirical evidence from five Gur and Kwa languages, we claim that these focus expressions have to be analysed as biclausal constructions even though they do not represent clefts containing restrictive relative clauses. First, we relativize the partly overgeneralized assumptions about structural correspondences between the out-of-focus part and relative clauses, and second, we show that our data do in fact support the hypothesis of a clause coordinating pattern as present in clause sequences in narration. It is argued that we deal with a non-accidental, systematic feature and that grammaticalization may conceal such basic narrative structures.
In this paper, we present the Multiple Annotation approach, which solves two problems: the problem of annotating overlapping structures, and the problem that occurs when documents should be annotated according to different, possibly heterogeneous tag sets. This approach has many advantages: it is based on XML, the modeling of alternative annotations is possible, each level can be viewed separately, and new levels can be added at any time. The files can be regarded as an interrelated unit, with the text serving as the implicit link. Two representations of the information contained in the multiple files (one in Prolog and one in XML) are described. These representations serve as a base for several applications.
Heterogeneity and standardization in data, use, and annotation : a diachronic corpus of German
(2005)
This paper describes the standardization problems that come up in a diachronic corpus: it has to cope with differing standards with regard to diplomaticity, annotation, and header information. Such highly heterogeneous texts must be standardized to allow for comparative research without (too much) loss of information.
The present study examines native and nonnative perceptual processing of semantic information conveyed by prosodic prominence. Five groups of German learners of English each listened to one of 5 experimental conditions. Three conditions differed in place of focus accent in the sentence and two conditions were with spliced stimuli. The experiment condition was presented first in the learners’ L1 (German) and then in a similar set in the L2 (English). The effect of the accent condition and of the length and position of the target in the sentence was evaluated in a probe recognition task. In both the L1 and L2 tasks there was no significant effect in any of the five focus conditions. Target position and target word length had an effect in the L1 task. Word length did not affect accuracy rates in the L2 task. For probe recognition in the L2, word length and the position of the target interacted with the focus condition.
We present a system for the linguistic exploration and analysis of lexical cohesion in English texts. Using an electronic thesaurus-like resource, Princeton WordNet, and the Brown Corpus of English, we have implemented a process of annotating text with lexical chains and a graphical user interface for inspection of the annotated text. We describe the system and report on some sample linguistic analyses carried out using the combined thesaurus-corpus resource.
When a statistical parser is trained on one treebank, one usually tests it on another portion of the same treebank, partly due to the fact that a comparable annotation format is needed for testing. But the user of a parser may not be interested in parsing sentences from the same newspaper all over, or even wants syntactic annotations for a slightly different text type. Gildea (2001) for instance found that a parser trained on the WSJ portion of the Penn Treebank performs less well on the Brown corpus (the subset that is available in the PTB bracketing format) than a parser that has been trained only on the Brown corpus, although the latter one has only half as many sentences as the former. Additionally, a parser trained on both the WSJ and Brown corpora performs less well on the Brown corpus than on the WSJ one. This leads us to the following questions that we would like to address in this paper: - Is there a difference in usefulness of techniques that are used to improve parser performance between the same-corpus and the different-corpus case? - Are different types of parsers (rule-based and statistical) equally sensitive to corpus variation? To achieve this, we compared the quality of the parses of a hand-crafted constraint-based parser and a statistical PCFG-based parser that was trained on a treebank of German newspaper text.
In this paper I will discuss the formation of different types of yes/no questions in Serbian (examples in (1)), focusing on the syntactically and semantically puzzling example (1d), which involves the negative auxiliary inversion. Although there is a negative marker on the fronted auxiliary, the construction does not involve sentential negation. This coincides with the fact that the negative quantifying NPIs cannot be licensed. The question formation and sentential negation have similar syntactic effects cross-linguistically. This has led to various attempts to formulate a unifying syntactic account of the phenomena (ever since Klima 1964). One striking fact about the two syntactic contexts is that both license weak NPIs (Negative Polarity Items). It has been suggested (cf. Laka 1990, Culicover 1991) that the derivation of both interrogatives and negatives involves the same type of functional projection PolP (polarity phrase). One such account of the formation of negative interrogatives in Serbo- Croatian is offered by Progovac (2005). She proposes that there are two PolPs optionally cooccurring in the same clause, in which both positive and negative polarity items check their positive or negative features (following Haegeman and Zanuttini (1991) feature-checking account of negative structures, and the insights of Brown(1999) on the negation in Russian). On her account, the negative auxiliary question in (1d), is the case when both polarity phrases are present. The higher has [-pos +neg] features, and the lower one (below TP) is [-pos -neg]. Although her account correctly predicts the ungrammaticality of (2a) in contrast with (1c), it wrongly predicts the (2b) to be grammatical. I will argue that Progovac’s theory regarding the nature of the PolP is wrong. It employs both the binary feature valuation on the polarity head and the hierarchical ordering of the two polarity phrases, which eventually leads to overgeneration. On the account presented here the nature of the question marker (li vs zar) is highly relevant. Notice that (1b) and (1d) express presuppositions regarding the truth value of the propositions. In this way they contrast with (1a) and (1c). In addition, the type (1b) (with the question particle zar) can introduce both the positive and negative presupposition as shown in (3), which, semantically, makes this construction compatible with negative auxiliary questions in English (4a). The polarity items licensed in the relevant structures are also of the same type in both languages. The fronted-negative-auxiliary questions (1d) in Serbian are only possible with the particle li. In this case the presupposition is exclusively positive. The peculiar question/focus marking function of li (in Bulgarian and Russian) is well known. However, it is always assumed that its focus marking role is not relevant for the formation of yes/no questions. This I believe is not correct. The syntactic explanation of the interpretational facts points to the following: A) The possibility of the separate lexical encoding (particle zar) of the ‘rhetorical’ yes/no questions in Serbian allows the embedding of both positive and negated sentences, in which case the (weak) NPIs can remain in local relation with the negated verb. B) Recall that Serbian is an NC language, which requires local/c-command relation between the verbal negative marker and the NPI. With the negative inverted auxiliary questions this condition is not met, and the licensing of an n-word is not possible. C) The impossibility of licensing a weak NPI (i-words in the examples below) is due to the nature of the question marker li. (1) a. Da li je Vera videla ikoga / nekoga / *nikoga? DA Q aux Vera see.part.F.Sg anyone someone noone “Did Vera see anyone/someone/noone?” b. Zar je Vera videla ikoga / nekoga / *nikoga? ZAR aux Vera see.part.F.Sg anyone someone noone “Is it really the fact that Vera saw anyone/someone?” c. Je li Vera videla ikoga / nekoga /*nikoga? aux Q Vera see.part.F.Sg anyone someone noone “Did Vera see anyone/someone/noone?” d. Nije li Vera videla *ikoga / nekoga / *nikoga? neg+aux Q Vera see.part.F.Sg anyone someone noone “Didn’t Vera see someone?”/ “Vera saw someone, didn’t she?” (2) a. *Nije li Vera videla nikoga? neg+aux Q Vera see.part.F.Sg noone b. *Nije li Vera videla ikoga? neg+aux Q Vera see.part.F.Sg anyone (3) a. Zar je Vera videla nekoga / ikoga? ZAR aux Vera see.part.F.Sg someone/anyone b. Zar Vera nije videla nekoga/nikoga? ZAR Vera neg+aux see.part.F.Sg someone/anyone (4) a. Didn’t Vera (NOT) see someone/anyone? b. Vera saw someone, didn’t she?
Since Donald Davidson’s seminal work “The Logical Form of Action Sentences” (1967) event arguments have become an integral component of virtually every semantic theory. Over the past years Davidson´s proposal has been continuously extended such that nowadays event(uality) arguments are generally associated not only with action verbs but with predicates of all sorts. The reasons for such an extension are seldom explicitly justified. Most problematical in this respect is the case of stative expressions. By taking a closer look at copula sentences the present study assesses the legitimacy of stretching the Davidsonian notion of events and discusses its consequences. A careful application of some standard eventuality diagnostics (perception reports, combination with locative modifiers and manner adverbials) as well as some new diagnostics (behavior of certain degree adverbials) reveals that copular expressions do not behave as expected under a Davidsonian perspective: they fail all eventuality tests, regardless of whether they represent stage-level or individual-level predicates. In this respect, copular expressions pattern with stative verbs like know, hate, and resemble, which in turn differ sharply from state verbs like stand, sit, and sleep. The latter pass all of the eventuality tests and therefore qualify as true “Davidsonian state” expressions. On the basis of these empirical observations and taking up ideas of Kim (1969, 1976) and Asher (1993, 2000), an alternative account of copular expressions (and stative verbs) is provided, according to which the copula introduces a referential argument for a temporally bound property exemplification (= “Kimian state”). Considerations on some logical properties, viz. closure conditions and the latent infinite regress of eventualities, suggest that supplementing Davidsonian eventualities with Kimian states may yield not only a more adequate analysis of copula sentences but also a better understanding of eventualities in general.
“Comments are very welcome!” This basic attitude and the many ways of implementing it contribute immensely to the fascination of engaging in scientific research. I am grateful to Theoretical Linguistics for providing a public platform for this kind of scholarly exchange and I thank all commentators for their thoughtful, stimulating, and often challenging contributions to my target article. My response will address two main issues that are raised by the commentaries. The first issue is shaped by a cluster of questions relating to ontology. The second issue concerns questions of methodology pertaining in particular to the problem of judging data.
The study offers a discourse-based account of the Spanish copula forms ser and estar, which are generally considered to be lexical exponents of the stage-level/individual-level contrast. It argues against the popular view that the distinction between SLPs and ILPs rests on a fundamental cognitive division of the world that is reflected in the grammar. As it happens, conceptual oppositions like “temporary vs. permanent” or “arbitrary vs. essential“ provide only a preference for the interpretation of estar and ser. In addition, the evidence for an SLP/ILP impact on the grammar turns out to be far less conclusive than is currently assumed. The study argues against event-based accounts of the ser/estar contrast in particular, showing that ser and estar pattern alike in failing all of the standard eventuality tests. The discourse-based account proposed instead assumes that ser and estar both display the same lexical semantics (which is identical to the semantics of English be, German sein, etc.); estar differs from ser only in presupposing a relation to a specific discourse situation. By using estar a speaker restricts his or her claim to a specific discourse situation, whereas by using ser, the speaker makes no such restriction. The preference for interpreting estar predications as denoting temporary properties and ser predications as denoting permanent properties follows from economy principles driving the pragmatic legitimation of estars discourse dependence. The analysis proposed in this paper can also account for the observation that ser predications do not give rise to thetic judgements. The proposal is couched in terms of the framework of DRT.
This paper profiles significant differences in syntactic distribution and differences in word class frequencies for two treebanks of spoken and written German: the TüBa-D/S, a treebank of transliterated spontaneous dialogs, and the TüBa-D/Z treebank of newspaper articles published in the German daily newspaper ´die tageszeitung´(taz). The approach can be used more generally as a means of distinguishing and classifying language corpora of different genres.
In the last decade, the Penn treebank has become the standard data set for evaluating parsers. The fact that most parsers are solely evaluated on this specific data set leaves the question unanswered how much these results depend on the annotation scheme of the treebank. In this paper, we will investigate the influence which different decisions in the annotation schemes of treebanks have on parsing. The investigation uses the comparison of similar treebanks of German, NEGRA and TüBa-D/Z, which are subsequently modified to allow a comparison of the differences. The results show that deleted unary nodes and a flat phrase structure have a negative influence on parsing quality while a flat clause structure has a positive influence.
This paper develops a framework for TAG (Tree Adjoining Grammar) semantics that brings together ideas from different recent approaches.Then, within this framework, an analysis of scope is proposed that accounts for the different scopal properties of quantifiers, adverbs, raising verbs and attitude verbs. Finally, including situation variables in the semantics, different situation binding possibilities are derived for different types of quantificational elements.
Multicomponent Tree Adjoining Grammars (MCTAG) is a formalism that has been shown to be useful for many natural language applications. The definition of MCTAG however is problematic since it refers to the process of the derivation itself: a simultaneity constraint must be respected concerning the way the members of the elementary tree sets are added. Looking only at the result of a derivation (i.e., the derived tree and the derivation tree), this simultaneity is no longer visible and therefore cannot be checked. I.e., this way of characterizing MCTAG does not allow to abstract away from the concrete order of derivation. Therefore, in this paper, we propose an alternative definition of MCTAG that characterizes the trees in the tree language of an MCTAG via the properties of the derivation trees the MCTAG licences.
In this paper eight tribes (Gyrophaenini, Placusini, Homalotini, Diestotini, Falagriini, Athetini, Lomechusini, and Oxypodini), 19 genera and 42 species are recognized. Four genera (Brachyglyptaglossa n. gen. [Homalotini], Trisporusa n. gen., Daccordiusa n. gen. [Lomechusini], and Antistydatusa n. gen. [Oxypodini]) and 37 species are described as new. Each new genus and species is illustrated. Placusa fauveli Pasnik, 2001, from Sydney, is placed in synonymy with Placusa tridens Fauvel, 1878, from Sydney. A new combination to Spallioda for Calodera carissima Oliff is proposed.
The vagaries of the lunar calendar are such that erev Pesach coincides with Shabbos infrequently and with an irregular pattern. The occurrence of erev Pesach on Shabbos gives rise to numerous complications with regard to the eating of chometz and its disposal, the proper mode of fulfilling the mitzvah of the Shabbos repasts and preparations for the seder. The following is intended for general guidance. The individual readers Moro de-Asro should be consulted with regard to any questions which may arise.
In many languages, a passive-like meaning may be obtained through a noncanonical passive construction. The get passive (1b) in English, the se faire passive (2b) in French and the kriegen passive (3b) in German represent typical manifestations. This squib focuses on the behavior of the get-passive in English and discusses a number of restrictions associated with it as well as the status of get.
The thesis is a study of the Jewish community of Leipzig, Germany over the course of the 20 th century. It begins with an overview of the Jews of the city until the rise to power of Adolf Hitler, emphasizing divisions with the Jewish community over the ideology of Zionism and between German-born and foreign-born Jews. It goes on to describe the lives of Jews as the Nazis come to state authority, the riots of November, 1938, and the gradual exclusion of Jews from professional and pubic life in the city. Jewish responses in education, politics and culture are examined, as are the decisions of many local people to emigrate. After the 1938 riots, exclusion began to shift to extermination, and the Jewish community found itself subject to deportation to camps in Eastern Europe. Most of those deported were murdered. Those who lived were able to do so because of good fortune, canny survival skills, or marriage to non-Jews. Jewish life, which had been an important part of the city, was systematically destroyed. After 1945, those few who survived in the city were joined by another handful of Jewish Leipzigers who survived the camps, and by some non-Leipzig Jews, to reform the Jewish community. A tiny percentage of the old Jewish world of Leipzig was left to rebuild. They did so, reestablishing institutions, reclaiming property, and beginning negotiations with the new authorities, the Soviet occupation and then the German Democratic Republic. The Jews of Leipzig continued some of their old concerns in this new world, negotiating with the government and among themselves the nature of their identities as Jews and as Germans. These negotiations were brought to a halt by a series of anti-Semitic purges in 1952 and 1953. The leadership of the Jewish community fled, as did many of their fellow-Jews. The behavior of the East German state at this point showed some surprising commonality with their Nazi predecessors. After the purges were over, those who remained began another process of rebuilding, this time in constant tension with a government that wanted to use them for propaganda purposes during the Cold War. With the fall of the communist regime in 1989-90, the Jewish community of Leipzig was able to chart its destiny again. The old issues of identity and community--among themselves and between Jews and their German neighbors--continue in a very different context.
In the year 2004 the ASFV celebrated its 50th anniversary holding a conference in Sulczyno, Kartuzy. This event offered the possibility to give an actual overview of forest resources and forest functions in Poland. The excursions of the meeting focused on the fascinating, diversified forest landscape formed by the Pomeranian phase of the Baltic glaciation. The Kartuzy Forest District is situated in the heart of the Kashubian Lakeland and the moraine hills. The landscape is not only characterized by the natural occurrence of Baltic beech forests but also by high diversity of soils and meso- and microclimatic de-viations providing habitats for rare plant species, including some plants typical of mountain regions. The tree species combination of the District is formed by pine, spruce, and beech. The oldest parts of the forests are legally protected as nature reserves.
Heteropteran communities in the canopies of Silver fir (Abies alba) and spruce (Picea abies) were studied at three lowland and three mountainous sites throughout Bavaria using flight-interception traps. At one lowland site sampling was extended to oak (Quercus petraea). A significantly higher number of species and specimens occurred on fir when compared to spruce. Including all sampled species, numbers on fir were even higher than on oak. Excluding tourists, oak was most species rich. Results demonstrate that fir, spruce, and oak harbour distinct communities. While specific communities including several rare species (e.g. Actinonotus pulcher, Psallus punctulatus) were found on fir, mainly generalists were found on spruce. Pinalitus atomarius, Cremnocephalus alpestris, Phoenicocoris dissimilis and Orius minutus significantly preferred fir. Therefore, with an increased cultivation of fir in lieu of spruce, an increase in Heteropteran diversity can be expected.
Urwald relict species – Saproxylic beetles indicating structural qualities and habitat tradition
(2005)
On the basis of the list of saproxylic beetles of Germany, the authors present a definition and list of “Urwald relict species”, comprising 115 beetles that are considered to be associated with primeval forest (“Urwald”) structures and features. We use the term “habitat tradition” to describe a continuity in supply of old growth dead wood and forest structures. The selection of species is made on behalf of the following criteria: relict records in Central Europe; attachment to continuity of deadwood resources and habitat tradition; continuity of old growth stand features like tree and deadwood maturity and di-versity; absence from cultivated Central European forest.
Comparison of three modelling approaches of potential natural forest habitats in Bavaria, Germany
(2005)
In the context of the EU Habitats Directive, which contains the obligation of environmental monitoring, nature conservation authorities face a growing demand for effective and competitive methods to survey protected habitats. Therefore the presented research study compared three modelling approaches (rule-based method with applied Bavarian woodland types, multivariate technique of cluster analysis, and a fuzzy logic approach) for the purpose of detecting potential habitat types. The results can be combined with earth observation data of different geometric resolution (ASTER, SPOT5, aerial photographs or very high resolution satellite data) in order to determine actual forest habitat types. This was carried out at two test sites, situated in the pre-alpine area in Bavaria (southern Germany). The results were subsequently compared to the terrestrial mapped habitat areas of the NATURA 2000 management plans. First results show that these techniques are a valuable support in mapping and monitoring NATURA 2000 forest habitats.
The map of “Regional natural forest composition by main tree species” (WALENTOWSKI et al. 2001) depicts Bavaria as a region largely predominated by the European beech (Fagus sylvatica). Analyses of climatope, hygrotope and trophotope of fir-dominated regional natural units make evident that the reasons for the preponderance of the European silver fir (Abies alba) are edaphic. In terms of regeneration vigour, growth and yield the fir particularly dominates in habitats with a combination of humus cover, acid-oligotrophic topsoils and clayey or waterlogged subsoils, where the beech usually exhibits stunted and malformed growth forms. This ecological preference has the effect that Bavarian Abies alba-forests are restricted to small patches within a matrix of potential natural vegetation formed by mixed deciduous-coniferous mountain forests. Within European Natura 2000 areas Abies- forests should be recorded carefully as special habitats. Their transitional character between temperate beech forests (habitat type 9130) and boreal spruce forests (habitat type 9410), the ecological preference of Abies alba as an endangered tree species and their sensitivity against environmental stressors, including changes in forest structure, air quality, and climate, make them important objects for nature conservation.
Consistent with its statutory responsibility, the National Library compiles the current ‘National Bibliography of Mauritius’ every year. The object of the current National Bibliography is to list every new work printed and published in and on Mauritius, to describe it in detail and give its bibliographical data and subject matter as precisely as possible. The National Bibliography is considered as a useful information tool, which gives access to the National Library’s Mauritiana Collection. It contains works printed in Mauritius during that period and deposited at the National Library, under the Legal Deposit Regulations and also those acquired through other sources. It includes books, society newsletters, government publications, current serials, reports, company accounts and reports, school magazines and newspapers. The first ‘National Bibliography of Mauritius’ for the years 1996 to 2000 was published in 2002. The second ‘National Bibliography of Mauritius’ for the years 2001 to 2003 was published in May 2005.
Theories of cognition that are based on information processing and representation are reactive (Rosen, 1985) or backwards looking, not anticipatory. In a previous article (Thibault, 2005a), I looked at the reasons why humans and bonobos do not need an innate language faculty in order to be minded, languaging beings. The present article takes up some of the questions explored there, but, it asks, on the other hand, what sort of a minded agent has language and what kind of account of language and more broadly meaning do we need to explain minded, languaged agents and the activities they participate in? Following Rosen (1985), I also take up and further develop a point first raised in Thibault (2004a: 187) on language as an anticipatory system, rather than a reactively ‘representational’ one (see also Bickhard, 2005).
A world revision of the four entedonine (Hymenoptera: Eulophidae: Entedoninae) genera of larval parasitoids of thrips (Thysanoptera) is presented: Ceranisus Walker, 1841, Entedonomphale Girault, 1915 stat. rev. (reinstated as a valid taxon from previous synonymy under Ceranisus, with type species E. margiscutum Girault, 1915 stat. rev.), Goetheana Girault, 1920, and Thripobius Ferrière, 1938. The following new generic synonymies are proposed: Cryptomphale Girault, 1917, Entedonastichus Girault, 1920, Pirenoidea Girault, 1922, and Thripoctenoides Erdös, 1954 under Entedonomphale. The proposed new combinations are as follows: Entedonomphale bicolorata (Ishii, 1933), E. nubilipennis (Williams, 1916), and Thripobius javae (Girault, 1917) from Ceranisus; Entedonomphale carbonaria (Erdös, 1954), E. dei (Girault, 1922), E. kaulbarsi (Yoshimoto, 1981), and E. mira (Girault, 1920) from Entedonastichus. New synonymies are proposed for the following species: Ceranisus vinctus (Gahan, 1932) under Ceranisus menes (Walker, 1839), Diglyphus aculeo Walker, 1848 under Ceranisus pacuvius (Walker, 1838); Ceranisus maculatus (Waterston, 1930) and Thripobius semiluteus Boucek, 1976 under Thripobius javae (Girault, 1917); Entedonastichus albicoxis (Szelényi, 1982) under Entedonomphale carbonaria (Erdös, 1954), and Entedonastichus gaussi (Ferrière, 1958) under Entedonomphale bicolorata (Ishii, 1933). Eleven new species are described: Ceranisus barsoomensis and C. votetoda (Australia), C. udnamtak (Nepal); Entedonomphale boccaccioi (USA), E. esenini (Madagascar), E. lermontovi (South Africa), E. quasimodo and E. zakavyka (Australia); Goetheana pushkini (Japan and Republic of Korea) and G. rabelaisi (Australia); and Thripobius melikai (China). Three species are excluded from Ceranisus: C. ancylae (Girault, 1917) (mistakenly listed in Ceranisus) as well as C. nigricornis Motschulsky, 1863 and C. semitestaceus Motschulsky, 1863, both taxa incertae sedis. New data are provided on the distribution and host associations of many of the species included in this review.
A taxonomic review of the species belonging to Bembidion Latreille, 1802 of Australia includes a key and descriptions of the species. Noinenclatorial acts proposed in this paper include: 1, taxa of new Status - Bembidion subgenus Sloanephila Netolitzky, 1931, valid subgenus, not consubgeneric with subgenus Philochtus Stephens, 1828; B. (Notaphocampa) riverinae Sloane, 1894 valid species, not subspecies of B. opulentum Nietner, 1858; 2, new synonyms B. (Notaphominis Netolitzky, 1931) = B. (Notaphocampa Netolitzky, 1914): 3, New subgenera - Australoemphanes, and Gondwanabembidion, 4, New species - B. (Ananotaphus) daccordii (South Australia, Mound Springs); 5, new subspecies - B. (Zeactedium) orbiferum giachinoi (New ZeaIand, North Island); 6, species transferred to Australoemphanes - B . (Ananotaphus) blackburni Csiki, 1928; 7, Species transferred to Gondwanabembidion - B . (Ananotaphus) proprium Blackburn, 1888. Conclusions of an informal phylogeographic study are: 1, the Auslralian continent was probably populated by the Bembidiina with relatively recent (Late Tertiary-Quaternary) invasions from the north by tropical lineages, while other lineages showing systematic relationships with African and South American taxa probably have an older, Gondwanian origin; and 2, some lineagas of predominantly Nearctic and Palaearctic taxa were also Gondwanian in origin.
The melibiose permease (MelB) of E.coli functions as a secondary-active symporter by using the electrochemical H+, Na+, or Li+ gradient to accumulate, e.g., melibiose [review in Pourcher et al. 1990a]. The global and primary objective of this thesis was to apply pre-steady state methods for the investigation of reaction rates of individual steps in the cycle of MelB. Especially the melibiose binding induced transition was investigated by the solid-supported membrane (SSM) technique [Seifert et al. 1993] in combination with a rapid solution exchange system [Pintchovius and Fendler 1999] and with the Stopped-flow technique [Roughton 1934]. To approach this goal, either wild-type or mutated MelB were purified and reconstituted into liposomes as described [Pourcher et al. 1995]. Although the orientation of the proteins is a critical factor for the activity of MelB, it was, so far, unknown. To determine the orientation of the proteins in the liposomes, single Cys mutants R139C and R141C [Abdel-Dayem et al. 2003] were selectively labeled with 3-(N-maleimidylpropionyl)biocytin (MPB) and analyzed by SDS-PAGE and Western Blot. The assay indicated that most of the proteins are inside-out (ISO) oriented permitting to relate the pre-steady state electrical and fluorescence signals to the reverse transport activity of MelB. The melibiose induced electrical signal was investigated in wild-type MelB with the SSM technique. The transporter was activated by a substrate concentration jump, and transient currents were measured. When the transporter was preincubated with Na+ at saturating concentrations, a charge translocation in the protein upon melibiose binding could still be observed. This result demonstrates that binding of the uncharged substrate melibiose triggers a charge displacement in the protein. Further analysis showed that the charge displacement is neither related to extra Na+ binding to the transporter, nor to the displacement of already bound Na+ within MelB. Electrogenic melibiose binding is explained by a conformational change with concomitant displacement of charged amino acid side chains and/or a reorientation of helix dipoles. A kinetic model is suggested, in which Na+ and melibiose binding are distinct electrogenic processes associated with approximately the same charge displacement. Melibiose binding is fast in the presence of Na+ (k > 50 s-1). Furthermore, two previously identified transport deficient mutants of loop 4-5, R141C and E142C [Abdel-Dayem et al. 2002, Séry 2002], were purified and extensively studied with the SSM. Whereas the electrical signals from control cysteine-less mutant showed a bi-exponential time course of decay, those from R141C or E142C consisted of only a single fast exponential component, and the slow decaying component associated with substrate translocation was missing. The electrical signals evoked by a melibiose concentration jump in the presence of Na+ were much smaller than the corresponding signals in C-less MelB. Furthermore, R141C lost the stimulating effect of melibiose on Na+ binding. Steady-state Trp fluorescence spectroscopy revealed impaired conformational changes after melibiose binding in the mutants and fluorescence resonance energy transfer (FRET) measurements indicated that the mutants still show cooperative modification of their sugar binding sites by Na+. These data suggest that loop 4-5 contributes to the coordinated interactions between the ion- and sugar binding site and participates in conformational changes after melibiose binding that are essential for the subsequent obligatory coupled translocation of substrates. By using the Stopped-flow technique, three different approaches were followed. First, the intrinsic Trp fluorescence of MelB, known to increase upon melibiose binding [Mus-Veteau et al. 1995], revealed a signal with a T 1 of ~15 ms in C-less. This time constant is of the same order of magnitude as that determined with the SSM method suggesting that Trp fluorescence and electrical signal are related processes. Conformation for this assumption came from the fact that the activation energies Ea for both processes are similar (around 45 KJ/mol). Second, by using the fluorescent sugar analog Dns2-S-Gal, which monitors events close to the sugar binding site [Maehrel et al. 1998], a signal with a T 1 of ~18 ms was recorded upon Na+ addition. Finally, the fluorescent dye MIANS was used to selectively label the single Cys mutant E365C of loop 10-11. Stopped-flow measurements revealed a melibiose-induced fluorescent signal with a T 1 of 45 ms. Since electrical measurements with the MIANS-labeled E365C excluded the possibility that the label is responsible for the slower kinetics, the conformational change detected by the MIANS fluorescence was assigned to a slow transition in the cycle of MelB after melibiose binding. Ea was determined to be 96 KJ/mol corroborating, thus, the hypothesis of a different process. In conclusion, it was possible to correlate the electrical and fluorescence signals to partial reactions of the transport cycle and to determine their rate constants. According to this new model, the melibiose-induced signal detected with the Trp and electrical measurements corresponds to a step preceding the carriers’ reorientation (3 <-> 3*, k ~ 65s-1), and the melibiose-induced signal detected with the MIANS fluorescence to the reorientation itself (3* <-> 4, k ~ 20s-1).
A taxonomic revision of the genus Syntrichia Brid. (Pottiaceae, Musci) in the Mediterranean Region and Macaronesia has been carried out, thus contributing to knowledge of its distinguisliing morphological characters, geographic distribution and nomenclature. Some 3000 specimens, including the most of type material, were studied. An identification key, morphological descriptions, photographs and numerous observations on taxonomic and nomenclatural problems of the 23 taxa accepted in the study area, are provided. New records for some countries of the Mediterranean basin and Macaronesia are given. Five new Synonyms are proposed. The designations of 11 new lectotypes are included and the name Syntrichia aciphylla var. calva J.J. Amann is excluded from the genus Syntrichia.
When one considers the results of social scientific surveys, secularisation in Germany seems to be a more or less linear process of erosion of what is traditionally named religiosity. The percentage of citizens who affirm that they are “religious”, believe in God or otherworldly beings, hope for life after death or participate regularly in the praxis of a religious community has been – by and large – steadily declining for decades. This decline has occurred over the succeeding generations: The younger the generation, the fewer “religious” people in it. But the process of secularisation is apparent not only in this persistent quantitative shrinkage from generation to generation. Above all it also manifests itself – this is the thesis of the article – in the transformation of the habitus formations and contents of faith of the generations. The essence of ongoing secularisation naturally is reflected most clearly in its contemporary state of development which is represented in the youngest adult generation. Therefore the analysis of this generation is particularly interesting for the sociology of religion. But the article does not confine to analyze this generation. After indicating some basic premises of the sociology of generations and the notion of secularisation presupposed in this paper, the succession of generations in Germany is outlined hypothetically, from the so-called generation of ´68 to the youngest adult generation, concluding with some remarks about the progress of secularisation.
Dialogue has become a fashionable word in the theological circles for quite some time now. However, there is a need to review what has been achieved so far. If it is significant, we should then review how much religious tension has been reduced so far. If it is not much, why has there been no progress. In this note I will deal with the issues relating to Hindu-Christian dialogue. I am using Christianity only as a reference point, and the issues raised do have a wider context as well. As far as Hindu-Christian dialogue is concerned, I am of the opinion that there has been hardly any progress all these years. Many academics and theologians have been involved in the exercise so far. The whole literature, over a long period of time, seems to follow a familiar pattern – a discussion on the theory of the dialogue, what should be included in a dialogue, who should and should not be involved in a dialogue, and ends with a lament that there is so very little progress. The problem, according to me, is that the dialogue does not even consider a need to discuss what is the basic difference between Hinduism and Christianity, and an inquiry into whether these come in the way of communal harmony. A dialogue is really not necessary if we are to discuss only what is similar between the two systems. ...
The Dalai Lama, in exile since 1959 in Hindu majority India, has continuously been taking a firm stand on giving importance to an inter-religious dialogue and interaction. He has made it absolutely clear that Buddhism represents just one of the many religious ways open for mankind. Nonetheless, he has always referred to the bond shared between Buddhism and Hinduism as a very special one and has experienced it as a religious tie. Both these religious streams belong to what is known as Bharatiya or Indo-genous Dharma. The Dalai Lama does not restrict his care for nurturing this common bond to a mere academic talk. In fact he has been taking active part in promoting this kind of inter-religious dialogue and has been showing a fiery political commitment as well. He thus took active part in the second World Hindu Congress organized by the Vishwa Hindu Parishad held in Prayag-Allahabad in the year 1979. According to official reports, the organizers in their welcome speech for the Dalai Lama were frank enough to admit that 2500 years ago, the Kashi Pandits (Kashi also known as Varanasi) had stopped Siddharta Gautama Buddha from entering the Vishwanath temple. It was also mentioned that for all these years, there has never been any letup in the conflict between Sanatani Hindus and Bauddhas, despite the fact that later on Shakya Muni was rewarded the status of avatara by Hindus. The fact that these very Kashi Pandits had invite one of the highest religious authorities of Buddhism - the Dalai Lama- to this congress should be seen as "a positive step towards reconciliation." The Dalai Lama was thus pleasantly surprised to see that the highest rung of the religious body of Hindus publicly acknowledged the divine status of Siddharta Gautama Buddha and recognized the presence of the Dalai Lama as a valuable contribution towards the reconciliation between the two religious streams. ...
A fresh look at the understanding of charity : with special reference to the present Indian practice
(2005)
The discussion of this paper is divided in two parts: Present understanding of Charity and a fresh look at the understanding of Charity particularly with a reference to the present Indian practice. As the major religious and theological perspectives specially from the Christian and the Islamic point of views are being dealt by other presentations in this seminar, therefore, the discussion here is limited only first, to the dictionary based linguistic meaning of Charity as understood in three main English speaking contexts and then (second), the Charity as practised in the Indian context. The new and revised deluxe edition of the Webster’s Encyclopaedic Unbridged Dictionary of the English Language has given the following meanings of Charity: 1)charitable actions, as almsgiving or performing other benevolent actions of any sort for the needy with no expectation of material reward: to devote ones life to charity, 2)something given to a person or persons in need; aims: she asked for work not charity, 3) a charitable act or work 4) a charitable fund, foundation, or institution: He left his estate to one of his charities, 5) benevolent feeling, esp. towards those in need or in disfavour: she looked so poor that we fed her out of charity, and 6) Christian love; agape 1 Cor. 13. The Chamber English Dictionary, the meanings of Charity gives as: universal love (N.T.): the disposition to think favourably of others, and do them good almsgiving: a usu. non profit-making foundation, institution, or cause, devoted to caring for those in need of help etc. According to Concise Oxford Dictionary Charity means: an organisation set up to provide help and raise money for those in need, the voluntary giving of money those in need, tolerance in judging others and love of humankind, typically in Christian context. These three set of meanings of Charity, represent the three English regions or contexts: American (Webster), Scottish (Chamber) and English (Oxford). The common important element in all for these three is, the Christian understanding of Charity, because all the three directly have referred to the Biblical usages of Charity in some forms. Here for the discussion of this paper, one can also add that even these usages are limited to the contextual understanding of the English world. Because language is also considered as an vehicle of a culture. But it is true that even the English speaking persons from the non-English world particularly of the Southern countries, (where English rulers have ruled in the past), understand the meaning of Charity more or less in the above sense only. ...
Islam, the Muslim traditions and the ulama in Central Asian societies are becoming increasingly important for assessing the situation in and around the region. To understand of the post Soviet Muslim republics it is nec-essary to know the Islamic heritage of the Soviet Union, i.e. the Islamic understanding and interpretation of Soviet official ulama which still influence the mind of the people and the contemporary Central Asian ulama. The official ulama were endeavouring to reconcile Islam with science and progress and to guarantee its survival in a modern environment, they served by an extremely energetic effort to preserve Islam at least in purity and integrity as religion and national sentiment and to prevent it from relapsing into deprivation and ignorance. The most important official Muslim religious figure, the Mufti of Tashkent Z. Babakhan interpreted Islam as a bulwark of progress, disseminator of knowledge, the religion of peace and friendship; portrayed the Prophet Muhammad as a “democrat, reformer and revolutionary, even a socialist”; reconciliation with socialism and communism.
In this article we dealt with the relations between the state and religion / Islam and its interpreters i.e., the ulama, their needs each other. As a case, with an original source, we focused on the time of the Mahmud II (1808-1839) The Ottoman reforms of the nineteenth century is reconciliation between Islam and Western civili-sation. In this process the ulama played key role by commenting Islam accordance with the need of the age or of the Ottoman Empire. The reformers, chiefly the Sultan and his close friends needed the support of the ulama to legitimate their reform programmes In this crucial stage the head of the ulama the Shaykhulislam, used his own religious knowledge and influence, derived from his office by writing a treatise to persuade the masses to accept the reforms. Applying the traditional virtue literature on the Ottoman dynasty he presented in this pamphlet one of the Western-minded Ottoman sultans as an ideal caliph-sultan. This attitude helped to transform the middle-aged Ottoman political structure and society into modern ages in Western line.
Experimente zum radiativen Elektroneneinfang (REC, Radiative Electron Capture), der Zeitumkehrung der Photoionisation, wie er in Stößen hochgeladener, relativistischer Schwerionen mit leichten Gasatomen auftritt, ermöglicht einen einzigartigen Zugang zum Studium der Photonen-Materie-Wechselwirkung im Bereich extrem starker Coulombfeldern. So ist die REC-Strahlung im relativistischen Bereich zum einen geprägt durch das Auftreten von höheren elektrischen und magnetischen Multipolordnungen und zum anderen durch starke Retardierungseffekte. In Folge dessen wurde der REC-Prozeß in den vergangen Jahren sehr detailliert untersucht, wobei sich die experimentelle und theoretische Forschung auf die Emissionscharakteristik der REC-Photonen konzentrierte, wie z.B. auf Untersuchungen von Winkelverteilungen und Linienprofilen. Mittlerweile kann der REC-Prozeß als ein - selbst für die schwersten Ionen - wohlverstandener Effekt angesehen werden. Allerdings entzog sich den Experimenten bislang eine zur Beschreibung der Photonenmission wesentlich Größe, näamlich die Polarisation der Strahlung. Die lineare Polarisation der REC-Strahlung, wie sie in Stößen zwischen leichten Atomen und den schwersten, hochgeladenen Ionen vorhergesagt wird, war der Gegenstand der vorliegende Arbeit, in der es erstmals gelang, die diese für den konkreten Fall des Einfangs in die K-Schale von nackten Uranionen nachzuweisen und im Detail zu untersuchen. Die hierzu notwendigen experimentellen Untersuchungen erfolgten am Speicherring ESR der GSI-Darmstadt für das Stoßsystem U92+ -> N2 und für Projektilenergien, die im Bereich zwischen 98 und 400 MeV/u lagen. Besonders hervorzuheben ist der Einsatz eines segmentierten Germaniumdetektors, der speziell für den Nachweis linear polarisierter Strahlung im Energiebereich oberhalb 100 keV entwickelte wurde. Die lineare Polarisation der Strahlung wurde hierbei durch eine Analyse der Comptonstreuung innerhalb des Detektors gewonnen. Die durch eine präzise Analyse der Comptonstreuverteilungen gewonnenen Daten zeigen eine ausgeprägte lineare Polarisierung der REC-Strahlung in der Streuebene, die zudem eine starke Abhängigkeit als Funktion der Stoßenergie und des Beobachtungwinkels aufweist. Der detaillierte Vergleich mit nicht-relativistischen und relativistischen Vorhersagen ermöglichte darüberhinaus den Nachweis für das Auftreten starker relativistischer Effekte, die sich allerdings depolarisierend auswirken. Das Experiment wurde am internen Target des ESR-Speicherrings durchgeführt, wobei der Photonennachweis mittels mehrerer Ge(i)-Detektoren erfolgte, die die Ionen-Target-Wechselwirkungszone unter Beobachtungswinkeln zwischen nahe Null und 150 Grad einsahen. Alle Photonendetektoren wurden in Koinizidenz mit einem Teilchendetektor betrieben, um so die volle Charakteristik des REC-Prozesses zu erfassen, also den Einfang eines Targetelektrons in die nackten Uranionen (U92+) unter Emission eines Photons. Für den Polarisationsnachweis entscheidend war der Einsatz eines Germanium-Pixel-Detektors, der abwechselnd unter den Winkeln von 60 und 90 Grad betrieben wurde. Dieser Detektor verfügt über eine 4x4 Pixelmatrix (Pixelgröße: 7x7 mm), wobei die elektronische Information jedes Pixels (Energiesignale und schnelle Zeitsignale) separat registriert und aufgezeichnet wurde. Hierdurch war es möglich Ereignisse, die koinzident in zwei Pixeln erfolgten, zu detektieren und zu analysieren. Dies ist die eigentliche Voraussetzung für den Nachweis der linearen Polarisation bei hohen Photonenenergien, bei dem die Abhängigkeit des differenziellen Wirkungsquerschnitts für Comptonstreuung von der linearen Polarisation der einfallenden Photonen ausgenutzt wird (siehe Klein-Nishina Formel Eq. 2.7). Der Nachweis der Comptonstreuung erfolgt hierbei durch die Detektion des Compton-Rückstoßelektrons (deltaE) und des gestreuten Comptonphotons (hw'), die jeweils separat, aber koinzident in zwei unterschiedlichen Segmenten des Detektors nachgewiesen werden. Hier sei betont, dass für Germanium bereits ab Photonenenergien von ca. 160 keV die Absorption der Strahlung durch den Compton-Effekt über die Photoabsorption dominiert und somit das Ausnutzen des Compton-Effekts prinzipiell eine sehr effektive Technik ist. Der Auswertung der Datenfkam wesentlich zugute, dass der Germanium-Detektor über eine im Vergleich zu Szintillations- oder Gaszählern gute Energieauflösung von ca. 1.8 keV bei 122 keV verfügt. Somit kann durch Bilden der Summenenergie hw = hw' + deltaE für koinzidente Ereignisse die Energie des einfallenden Photons (hw) rekonstruieren werden und als zwingende Bedingung dafür herangezogen werden, dass es sich bei dem Ereignis im Detektor um ein Compton-Event gehandelt hat. Für den Fall linearer Polarisation ist eine wesentliche Aussage der Klein-Nishina-Formel, dass die maximale Intensität für die Compton gestreuten Photonen senkrecht zur Polarisationsebene zu erwarten ist. Tatsächlich zeigen bereits die während des Experiments aufgenommenen Rohdaten für den Fall der untersuchten REC-Strahlung, die durch den Einfang in die K-Schale des Projektils entsteht, dass es sich hierbei um eine stark polarisierte Strahlung handelt, wobei eine erhöhte Intensität für Comptonstreuung senkrecht zur Stoßebene (für den REC-Prozeß definiert durch die Ionenstrahlachse und den Impuls des REC-Photons) festgestellt wurde (vgl. Fig. 7.3). Zur genauen qualitativen Analyse der Meßdaten wurden alle möglichen Pixelkombinationen der (4x4) Detektorgeometrie ausgewertet, wobei jedoch koinzidente Ereignisse benachbarter Segmente ausgeschlossen wurden, um den hier vorhandenenen Einfluß elektronischer Übersprecher zu eliminieren. Zudem erfolgte die Analyse der Daten unter Berücksichtigung verschiedenster Effekte, die einen Einfluß auf die Nachweiseffizienzen für die Compton gestreuten Photonen haben könnten. An prominenter Stelle ist hier die Korrektur zu nennen, die durch die Detektordicke von 1,5 cm und der Pixelgröße von 7x7 cm2 hervorgerufen wird. Zu betonen ist hier, dass für die Auswertung nur relative Effizienzen eine Rolle spielen und so der Einfluß systematischer Fehler, hervorgerufen durch Effizienzkorrekturen, stark reduziert werden konnte (für eine so gewonnene, vollständige Compton-Streuverteilung sei auf Abbildung 9.1 verwiesen, in der die Intensitätsverteilung für Compton-Streuung dargestellt ist). Es sei auch hervorgehoben, dass der Nachweis der Polarisation durch Messungen von vollständigen Compton-Intensitätverteilung im Detektor erfolgte, was das hier diskutierte Experiment wesentlich von konventionellen Polarisationsexperimenten für harte Röntgen- und gamma-Strahlung unterscheidet. Üblicherweise wird in diesen Experimenten die Comptonstreuung ausschließlich in der Reaktionsebene und senkrecht dazu nachgewiesen. Generell weisen die in der vorliegenden Arbeit gewonnen Compton-Streuverteilungen für den K-REC-Prozeß ein ausgeprägtes Maxium senkrecht zur Reaktionsebene auf und bestätigen somit den bereits aus den Rohdaten abgeleiteten Befund, dass die Polarisationsebene der KREC Strahlung in der Reaktionsebene des Stosses liegt. In der Tat kann dieser Befund für alle Energien und Beobachtungswinkel bestätigt werden, die in dem hier diskutierten Experiment verwendet wurden. Hier sei zudem darauf hingewiesen, dass es durch die Erfassung der vollständigen Compton-Streuverteilung möglich war, die Orientierung der Polarisationsebene in Bezug auf die Stoßebene mit hoher Präzision zu erfassen. So konnte z.B. bei der Stossenergie von 400 MeV/u und dem Winkel von 90 Grad, die Orientierung der Comptonstreuverteilung in Bezug auf die Stoßebene zu ph=90 Grad bestimmt werden. Dieser Befund könnte für die Planung zukünftiger Experimente zum Nachweis polarisierter Ionenstrahlen entscheidend sein, da eine Abweichung von der ph = 90 Grad Symmetrie nur durch das Vorhandensein polarisierter Teilchen erklärt werden kann. Dieser Effekt, der in neuesten theoretischen Behandlungen im Detail untersucht wurde, stellt gleichsam einen neuen Zugang zur Bestimmung des Polarisationsgrads der Projektile dar. Hierdurch wird die Stärke der hier angewandten Technik verdeutlicht, die auf dem Einsatz eines ortsempfindlichen Germanium-Pixel- Detektors beruht. Die Bestimmung des genauen Polarisationsgrades für die K-REC-Strahlung erfolgte durch eine X2-Anpassung der Klein-Nishina-Formel an die experimentellen Daten. Die hieraus resultierenden Daten zeigen für alle Strahlenergien und Beobachtungsgwinkel eine starke Polarisation von etwa 80%, wobei die experimentelle Unsicherheit im 10% Bereich liegt. Letztere ist im wesentlichen auf die statistische Genauigkeit zurückzuführen. Die Daten wurden zudem eingehend mit theoretischen Vorhersagen verglichen. Die Theorie stützt sich auf eine vollständige relativistische Beschreibung des REC-Prozesses unter Verwendung exakter Wellenfunktionen für das Kontinuum und den 1s Zustand in wasserstoffartigem Uran. Typischer weise mußten bei den Rechnungen sowohl elektrische wie auch magnetische Multipolterme bis hin zu L=20 verwendet werden, um Konvergenz zu erreichen. Der Vergleich zeigt eine hervorragende Übereinstimmung zwischen Experiment und Theorie. Zudem verdeutlicht der Vergleich mit der ebenfalls diskutierten Vorhersage der nicht-relativistischen Dipolnäherung die Bedeutung relativistischer Effekte (vor allem das Auftreten höherer elektrischer und magnetischer Multipole), die für die Emission der REC-Strahlung bei hohen, relativistischen Energien und hohem Z charakteristisch sind. Offensichtlich wirken sich diese Effekte stark depolarisierend aus. Dass in der Tat eine Zunahme der depolarisierenden Effekte mit einer Zunahme der Strahlenergie verbunden ist, wird auch durch die Daten dokumentiert, die für den Beobachtungswinkel von 60 Grad als Funktion des Projektilenergie untersucht wurden. Die in der vorliegenden Arbeit gewonnenen Resultate für die Polarisation der REC-Strahlung ebenso wie die neuartige Experimenttechnik, die hierbei zum Einsatz kam, lassen für die nahe Zukunft eine Serie von weiteren Polarisations-Experimenten erwarten. Hierbei könnte der REC-Strahlung und deren Polarisation als Mittel zur Diagnostik und zum Nachweis des Polarisationsgrades gespeicherter Ionenstrahlen eine Schlüsselrolle zukommen. Als Detektorsysteme werden hierzu zwei-dimensionale Germanium- und Silizium-Streifen-Detektoren zum Einsatz kommen bzw. Kombinationen aus zweidimensionalen Silizium- und Germanium-Detektoren, sogenannte Compton-Teleskope. Diese Compton-Polarimeter, die gegenwärtig für neue Experimentvorhaben am ESR-Speicherring entwickelt werden, verfügen über eine wesentlich verbesserte Ortsauflösung (z.B. 1x1 mm2) und somit über eine wesentlich gesteigerte Nachweiseffizienz für die Comptonstreuung (ein bis zwei Größenordnungen). Hierdurch sollte es möglich sein, den für Polarisationexerperimente zugänglichen Energiebereich wesentlich auszudehnen, sodass selbst die charakteristische Strahlung der Schwerionen (ca. 50 bis 100 keV) für solche Experimente zugänglich wird.
The development of a drug product, beginning with the synthesis of the drug substance through approval for marketing, may take up to 15 years and a total amount of investment of up to half a billion Euro. After the discovery of a potential drug substance, many different investigations have to be performed: e.g. characterization of the physical-chemical properties, the pharmacological and toxicological profile and, especially relevant for this work, the development of the first dosage forms. After achieving these steps, first investigations in human studies can be carried out. After a positive assessment of the benefit to risk ratio, further investigations, such as food effects on the pharmacokinetics, multiple dosing studies and further studies on patients can be implemented. After successfully completing this second part the new drug product can be approved. With broader clinical experience it often becomes apparent that changes in relevant aspects of the formulation of the registered drug product e.g. excipients, concentration of the drug substance or excipient versus drug substance ratio, are necessary to optimise the therapy. This often leads to additional clinical investigations and a new registration, a procedure which is time and cost intensive. A possible way to reduce the financial and time investments, is to establish an appropriate in vivo- in vitro correlation (IVIVC). If it is possible to predict the in vivo performance of a drug product adequately with in vitro methods (dissolutions tests), it will no longer be necessary to perform additional clinical investigations. In this work, IVIVCs were investigated for three different drug substances and several different types of formulations.... ...Results of this work clearly show that successful IVIVCs can be achieved for the fasted state using biorelevant dissolution media. A prerequisite of achieving a good IVIVC is the availability of in vivo data of a reference product (i.v., oral solution or IR) tested within the same group of volunteers as the product of interest. Only with this procedure, one can obtain adequate IVIVCs for drug substances with high inter-individual variability of the plasma concentrations and with high first-pass metabolism. This work also shows that predictions of the in vivo behavior of a modified release dosage form after administration with a high fat meal are more difficult to obtain. This is mainly related to an absence of a medium, which could mimic the situation of the fed stomach adequately. Ensure plus®, which was chosen in this work, failed to simulate the fed stomach adequately in several cases; it suppressed the release of rosiglitazone from lipid formulations and led to rapid disruption of the HPMC-matrix of the 5-ISMN Geomatrix formulations. Future work should be directed towards optimization of the test media in the BioDis apparatus. This work clearly shows the inability of Ensure plus® to predict the in vivo performance of a drug under fed state conditions and indicates that alternative media must be developed. It is known that the pH of the stomach rises up to six after the intake of a meal. During the following hours the pH decreases until reaching the baseline value of approximately 1.8. One possibility of simulating the fed state stomach more precisely will be to divide the overall residence time into 4 different parts: 1. half a hour at pH 6 2. half a hour at pH 4 3. one hour at pH 3 4. two hours at pH 1.8 Another option is not only to modify the pH of the medium, but also to change its composition. During the decomposition of the food contents, the composition of the gastric juice changes, the ionic strength, the buffer capacity and the osmolarity rises, while the pH value decreases. A third possibility will be the addition of enzymes, mainly pepsin, lipases and amylases. Again, the quantity of the enzymes differs during the residence time of the food in the stomach. Highest quantities are expected in the first two hours after food intake and decreases in the remaining two hours. Another issue of this work was an assessment of the two dissolution apparatus, Paddle and BioDis. In general, the choice of the dissolution apparatus should be done primarily with respect to the solubility behavior of the drug substance. For high soluble drugs the USP apparatus II, Paddle, is sufficient (e.g. diltiazem or 5-ISMN). In cases of a poorly soluble drug (rosiglitazone), where the release strongly depends on the medium used, the USP apparatus III (BioDis) is favored, due to the advantage of simulating the GI-tract with a gradient of different dissolution media, each simulating one part of the GI-tract. In summary, the results of this work indicate that it is acurrently possible to predict fasted state behavior of a variety of controlled release products using in vitro tests. Prognoses was also made in terms of predicting food effects on the behavior of controlled release products, although it is clear that the media compositions will have to be revised to establish releiable predictive methods for the fed state.
Hard physics in STAR
(2005)
The hot and dense matter created in high-energy nuclear collisions is believed to undergo a transition into a deconfined phase where partonic degrees of freedom determine the dynamics of the medium. High-p⊥ partons, that are produced in the initial collisions between nucleons of the incoming nuclei, lose energy as they propagate through the medium. This effect, called jetquenching, is observed in high-p⊥ particle spectra, in azimuthal correlations with the reaction plane (elliptic flow) and jet-like two-particle correlations.
STAR consists of tracking detectors and electromagnetic calorimetry with large and azimuthally symmetric acceptance and is exceptionally well suited for single particle detection and correlation studies at high p⊥. In the last five years, it has collected a large dataset including Au+Au and Cu+Cu collisions at different energies and reference data from p+p and d+Au collisions.
We present particle spectra and two-particle correlations at high-p⊥, and relate these measurements to the properties of the medium.
The CERN Axion Solar Telescope (CAST) is searching for axions produced in the Sun's core by the Primakoff process. CAST is using a decommissioned Large Hadron Collider (LHC) test magnet where axions could be converted back into X-rays with energies up to 10 keV. Analysis of the 2003 data showed no signal above background implying an upper limit for the axion-photon coupling constant gagg < 1.16 X 10 ^-10 GeV exp -1 at 95% C.L. for ma . 0.02 eV [1]. The higher quality 2004 data is presently under analysis. CAST Phase II is scheduled to start in late 2005. This will be the first step in extending CAST's sensitivity to axion rest masses up to ~ 1 eV.
We compute neutrino emissivities, specific heat, and the resulting cooling rates in four spin-one color superconductors: color-spin locked, planar, polar, and A phases. In particular, the role of anisotropies and point nodes in the quasiparticle excitation spectra are investigated. Furthermore, it is shown that the A phase exhibits a helicity order, giving rise to a reflection asymmetry in the neutrino emissivity.
The J/psi-hadron interaction is a key ingredient in analyzing the J/psi suppression in hot hadronic matter as well as the propagation of J/psi in nuclei. As a first step to clarify the J/psi-hadron interactions at low energies, we have calculated J/psi-pi, J/psi-rho and J/psi-nucleon scattering lengths by the quenched lattice QCD simulations with Wilson fermions for beta=6.2 on 24^3*48 and 32^3*48 lattices. Using the Luscher's method to extract the scattering length from the simulations in a finite box, we find an attractive interaction in the S-wave channel for all three systems: Among others, the J/psi-nucleon interaction is most attractive. Possibility of the J/psi-nucleon bound state is also discussed.
We present quantitative and qualitative arguments in favor of the claim that, within the present cosmological epoch, the U(1)gamma factor in the Standard Model is an effective manifestation of SU(2) pure gauge dynamics of Yang-Mills scale Lambda ~ 10^-4 eV. Results for the pressure and the energy density in the deconfining phase of this theory, obtained in a nonperturbative and analytical way, support this connection in view of large-angle features inherent in the map of the CMB temperature fluctuations and temperature-polarization cross correlations.
There is a growing body of evidence that indicates common environmental pollutants are capable of disrupting reproductive and developmental processes by interfering with the actions of endogenous hormones. Many reports of endocrine disruption describe changes in the normal development of organs and tissues that are consistent with genetic damage, and recent studies confirm that many chemicals classified to have hormone-modulating effects also possess carcinogenic and mutagenic potential. To date, however, there have been no conclusive examples linking genetic damage with perturbation of endocrine function and adverse effects in vivo. Here, we provide the first evidence of DNA damage associated with the development of imposex (the masculinization of female gastropods considered to be the result of alterations to endocrine-mediated pathways) in the dog-whelk Nucella lapillus. Animals (n = 257) that displayed various stages of tributyltin (TBT)-induced imposex were collected from sites in southwest England, and their imposex status was determined by physical examination. Linear regression analysis revealed a very strong relationship (correlation coefficient of 0.935, p < 0.0001) between the degree of imposex and the extent of DNA damage (micronucleus formation) in hemocytes. Moreover, histological examination of a larger number of dog-whelks collected from sites throughout Europe confirmed the presence of hyperplastic growths, primarily on the vas deferens and penis in both TBT-exposed male snails and in females that exhibited imposex. A strong association was found between TBT body burden and the prevalence of abnormal growths, thereby providing compelling evidence to support the hypothesis that environmental chemicals that affect reproductive processes do so partly through DNA damage pathways.
Previous investigations have shown that bisphenol A (BPA) induces a superfeminization syndrome in the freshwater snail Marisa cornuarietis at concentrations as low as 1 μg/L. Superfemales are characterized by the formation of additional female organs, enlarged accessory sex glands, gross malformations of the pallial oviduct, and a stimulation of egg and clutch production, resulting in increased female mortality. However, these studies were challenged on the basis of incomplete experimentation. Therefore, the objective of the current approach was to bridge several gaps in knowledge by conducting additional experiments. In an initial series of experiments, study results from the reproductive phase of the snails were evaluated in the sub-micrograms per liter range. Before and after the spawning season, superfemale responses were observed [NOEC (no observed effect concentration) 7.9 ng/L, EC10 (effective concentration at 10%) 13.9 ng/L], which were absent during the spawning season. A further experiment investigated the temperature dependence of BPA responses by exposing snails at two temperatures in parallel. The adverse effect of BPA was at least partially masked at 27°C (EC10 998 ng/L) when compared with 20°C (EC10 14.8 ng/L). In M. cornuarietis, BPA acts as an estrogen receptor (ER) agonist, because effects were completely antagonized by a co-exposure to tamoxifen and Faslodex. Antiandrogenic effects of BPA, such as a significant decrease in penis length at 20°C, were also observed. Competitive receptor displacement experiments indicate the presence of androgen- and estrogen-specific binding sites. The affinity for BPA of the estrogen binding sites in M. cornuarietis is higher than that of the ER in aquatic vertebrates. The results emphasize that prosobranchs are affected by BPA at lower concentrations than are other wildlife groups, and the findings also highlight the importance of exposure conditions.
Since its recognition as an endothelium-derived relaxing factor, the control and consequences of nitric oxide (NO) production have been investigated intensely. We know now that NO is not simply a vasodilator or regulator of smooth muscle tone but is a potent anti-platelet agent, neuromodulator and regulator of gene expression. NO is synthesized from the amino acid Larginine by a family of enzymes termed NO synthases (NOS). The ‘endothelial’ (eNOS or NOS III) and ‘neuronal’ (nNOS, NOS I or bNOS) NOS isoforms, which were named after the tissues in which they were first identified, are expressed constitutively and are generally regulated by Ca2+/calmodulin (CaM). Endothelium-derived NO is thought to be responsible for maintaining the vasculature in an anti-atherosclerotic state and a decrease in the bioavailability of NO (a state generally referred to as endothelial dysfunction) results in “proatherosclerotic” alterations in vascular gene expression. Recently it has become clear that the activity of eNOS is largely determined by its association with regulatory proteins as well as by the phosphorylation of the enzyme on serine, threonine and possibly tyrosine residues. Moreover, the enzyme can be “uncoupled” i.e. transformed from a NO generating to a superoxide (O2-)-generating enzyme, which would be expected to attenuate vasodilator responses and enhance vascular inflammation. The aim of this thesis was to study the consequences of phosphorylation on specific serine, threonine and tyrosine residues on the activity and intracellular localisation of eNOS and in particular to determine whether a phospho-switch for eNOS uncoupling exists. eNOS is phosphorylated under basal conditions and its serine phosphorylation can be enhanced following cell stimulation with hemodynamic stimuli such as cyclic stretch and fluid shear stress as well as by hormonal stimuli such as histamine and bradykinin. Our group has previously demonstrated the importance of Ser1177 in the activation of eNOS and here I set out to determine the relative importance of phosphorylation on Ser633 and Ser114. By generating point mutants in which serine was replaced by either alanine (nonphosphorylatable mutants) or aspartate (phosphomimetic mutants) it was observed that the activity of the S633D and S114A eNOS mutants exhibited an 2-fold increase over the activity of the wild-type enzyme or either of the S633/634A or S114D eNOS mutants as determined by monitoring the conversion of L-arginine to L-citrulline. eNOS is basally phosphorylated on Thr495 and stimulation of endothelial cells with Ca2+-elevating agonists generally results in the transient dephosphorylation of this residue. The latter is essential to allow the binding of calmodulin to the enzyme and is the actually initiating step in the generation of NO. Correspondingly, the T495A eNOS mutant can be activated at lower Ca2+ and calmodulin concentrations than the T495D mutant. However, some eNOS mutants (T494A/S1177D and T495A) showed an enhanced ability to generate O2- in a NOS inhibitor-sensitive manner suggesting that the phosphorylation of the enzyme may also play a role in the uncoupling process. To determine the physiological relevance of eNOS dephosphorylation on Thr495 we assessed the consequences of treating cells with oxidised low-density lipoprotein (ox-LDL) on eNOS phosphorylation as well as on the eNOS-dependent generation of NO and O2-. Oxidised LDL concentration- and time-dependently decreased phosphorylation of eNOS on Thr495 and led to a concomitant decrease in cellular levels of cyclic GMP and an enhanced production of O2 - compared to cells treated with native LDL. Alterations in the activity of protein kinase C (PKC) were related to the change in eNOS Thr495 phosphorylation. There was not only the basal activity of PKCα inhibited by ox-LDL but the PKC activator phorbol-12-myristate-13-acetate also failed to elicit the phosphorylation of Thr495 in ox-LDL-treated endothelial cells. The dephosphorylation of eNOS on Thr495 in response to the addition of ox-LDL was not associated with an increase in the binding of calmodulin to eNOS, an association usually necessary for the activation of eNOS. Moreover, following treatment with ox-LDL for 24 hours eNOS was no longer detected at the plasma membrane but was redistributed to the cytosol indicating that ox-LDL may disrupt the eNOS signalling complex or signalosome. To date the role played by the tyrosine phosphorylation of eNOS in the regulation of its activity or intracellular association is controversial. However, during the preparation of this thesis we have been able to demonstrate a link between the tyrosine phosphorylation of eNO and the activation of the tyrosine kinases Src and PYK2. The application of fluid shear stress to endothelial cells resulted in the activation of Src and PYK2 as well as in the association of PYK2 with eNOS. Co-expression of eNOS and PYK2 led to the putative identification of Tyr657 as a potential modulatory site. Mutating eNOS at Tyr657 to Asp or Glu resulted in the localisation of the mutant eNOS predominantly in the cytoskeleton and also in a complete inactivation of the enzyme. The Y657F mutants, on the other hand, did not demonstrate any marked alteration in the activity when compared with the wild-type eNOS. However, the In conclusion, the results describe in this thesis indicate that eNOS is regulated by phosphorylation at multiple sites. Depending on the phosphorylation site involved phosphorylation can inhibit or activate NO production or even uncouple the enzyme so that it generates O2-. While the phosphor-status of eNOS on Ser114 and Ser633 influenced NO release they did not contribute to O2 - production and the dephosphorylation of Thr495 seems sufficient to uncouple eNOS. Cell treatment with ox-LDL, which is known to increase eNOS-derived O2- output was correlated with a dephosphorylation of Thr495 as well as a decrease in the activity of the kinase that phosphorylates this site i.e., PKCα. The phosphorylation status of all the eNOS serine and threonine residues studied however did not influence the ability of the enzyme to dimerise, indicating that contrary to previously published reports the eNOS dimer is highly stable in endothelial cells. The tyrosine phosphorylation of eNOS was not initially expected to play a determinant role in the regulation but rather to facilitate the docking of associated regulatory proteins. However, Tyr657 seems to play a critical role in the generation of NO as its mutation resulted in the generation of a completely inactive enzyme as well as in an apparent intracellular mislocalisation of the protein. The physiological relevance of these findings remain to be further elucidated.
Phage display selection of HIV specific conserved mimotopes with IgG from long-term non-progressors
(2005)
Poster presentation Background The aim of this study is to identify conserved epitopes of HIV-1 neutralizing antibodies in polyclonal plasma from LTNP to finally derive vaccine candidates. Materials and methods The presence of neutralizing antibodies in 9 LTNP sera was proved by in vitro neutralization assays. Phage displayed peptide libraries were screened with LTNP IgG. HIV-specific mimotopes were analyzed for homology to the gp120 structure by a software (3DEX) especially developed for this purpose. Mice were immunized with interesting phages and their sera were analyzed for neutralizing activities against HIV-1. Results After biopannings, between 19% and 75% HIV-specific phage clones were identified by ELISA. Mimotope sequences were identified and could be aligned by 3DEX to linear or conformational epitopes on gp120. A peptide specific immune response was detected in sera of immunized mice. The first mice sera analyzed showed neutralizing activities against HIV-1. Conclusion Mimotopes could be selected from LTNP sera that represent conformational epitopes on gp120. Those ones inducing neutralizing antibodies upon immunization potentially are suited to derive vaccine candidates.
Current thinking on African conflicts suffers from misinterpretations oversimplification, lack of focus, lack of conceptual clarity, state-centrism and lack of vision). The paper analyses a variety of the dominant explanations of major international actors and donors, showing how these frequently do not distinguish with sufficient clarity between the ‘root causes’ of a conflict, its aggravating factors and its triggers. Specifically, a correct assessment of conflict prolonging (or sustaining) factors is of vital importance in Africa’s lingering confrontations. Broader approaches (e.g. “structural stability”) offer a better analytical framework than familiar one-dimensional explanations. Moreover, for explaining and dealing with violent conflicts a shift of attention from the nation-state towards the local and sub-regional level is needed.
Natural resources in sub-Saharan Africa suffer from a bad reputation. Oil and diamonds, particularly, have been blamed for a number of Africa’s illnesses such as poverty, corruption, dictatorship and war. This paper outlines the different areas and transmission channels of how this so-called “resource curse” is said to materialize. By assessing empirical evidence on sub-Saharan Africa it concludes that the resource curse theory fails to sufficiently explain why and how several countries have not or only partly been affected by the “curse”. Theoretically, the paper argues that whether or not natural resources are detrimental to a country’s socio-economic and political development depends on a number of contextual variables, divided into country-specific conditions and resource-specific conditions (type, degree/level of abundance and dependence, resource revenue management, involved companies etc.). Methodologically, a future research agenda needs to examine the complex interplay of these contextual variables by adding sophisticated comparative research designs, especially “small and medium N” comparisons, to the tool box which has been widely confined to the juxtaposition of “large N” and country case studies.
Amblyopia is a developmental disorder of the visual system that leads to reduced vision in one or both eyes. People suffering from amblyopia show different perceptual deficits like reduced contrast sensitivity, reduced or no stereopsis, spatial uncertainty, and spatial and temporal distortions when viewing with the amblyopic eye. In the following thesis, different psychophysical methods are used to investigate anomalous perception of amblyopic participants in detail with the main focus on the perception of temporal instability. In the qualitative experimental paradigms it is shown that temporal instability is mainly perceived by strabismic and strabismic-anisometropic amblyopes. The temporal deficits occur only at spatial frequencies higher than 1.6 c/deg, and are perceived in addition to the spatial distortions. Illusory colours sometimes accompany the temporal distortions. There seems to be a relationship between crossed hand and eye dominance and the perception of temporal instability. In the quantitative experiments it is shown that temporal instability in amblyopic perception has a negative impact on the performance in psychophysical tasks. Amblyopes perceiving temporal instability show enhanced spatial uncertainty and spatial distortions for different types of stimulus presentation (auditive vs. visual) when compared to amblyopes without temporal instability. This might be due to deficits in auditive-visual mapping. These deficits in auditory-to-visual mapping suggest an impairment of the dorsal “where” pathway. Thus, it might be that amblyopes with temporal distortions have deficits in the dorsal pathway that come up in addition to the known deficits of the ventral “what” pathway and are related to the perception of temporal instability. The different results of the experiments found in this thesis seem to confirm this hypothesis. Studies using functional imaging techniques might be appropriate for a further investigation of amblyopic deficits involving the dorsal pathway.
The article explores the increasing gap between the cultural dynamics of transnationalization in Germany and the national self-perception of the German society. While concepts of “in-migration” (Zuwanderung) and ”integration” still stick to notions of the nation-state as being a ”container” embracing and controlling a population and a culture of its own, the various processes of material and imaginary mobility across the national borders contradict and challenge this notion as well as its political implications. By drawing on the transnational lifeworlds and the cultural productivity of migrants, anthropological research has made important contributions to render visible this challenge. It is argued, however, that an all too exclusive focus on migration may, in fact, rather conceal the wider effects of transnationalisation and cultural globalisation on the society and its cultural fabric as a whole.
We study the phase diagram of dense, locally neutral three-flavor quark matter within the framework of the Nambu--Jona-Lasinio model. In the analysis, dynamically generated quark masses are taken into account self-consistently. The phase diagram in the plane of temperature and quark chemical potential is presented. The results for two qualitatively different regimes, intermediate and strong diquark coupling strength, are presented. It is shown that the role of gapless phases diminishes with increasing diquark coupling strength.
The paper considers optimal monetary stabilization policy in a forward-looking model, when the central bank recognizes that private-sector expectations need not be precisely model-consistent, and wishes to choose a policy that will be as good as possible in the case of any beliefs that are close enough to model-consistency. It is found that commitment continues to be important for optimal policy, that the optimal long-run inflation target is unaffected by the degree of potential distortion of beliefs, and that optimal policy is even more history-dependent than if rational expectations are assumed. JEL Classification: E52, E58, E42
We have used the SLIMCAT 3-D off-line chemical transport model (CTM) to quantify the Arctic chemical ozone loss in the year 2002/2003 and compare it with similar calculations for the winters 1999/2000 and 2003/2004. Recent changes to the CTM have improved the model's ability to reproduce polar chemical and dynamical processes. The updated CTM uses σ-θ as a vertical coordinate which allows it to extend down to the surface. The CTM has a detailed stratospheric chemistry scheme and now includes a simple NAT-based denitrification scheme in the stratosphere.
In the model runs presented here the model was forced by ECMWF ERA40 and operational analyses. The model used 24 levels extending from the surface to ~55km and a horizontal resolution of either 7.5° x 7.5° or 2.8° x 2.8°. Two different radiation schemes, MIDRAD and the CCM scheme, were used to diagnose the vertical motion in the stratosphere. Based on tracer observations from balloons and aircraft, the more sophisticated CCM scheme gives a better representation of the vertical transport in this model which includes the troposphere. The higher resolution model generally produces larger chemical O3 depletion, which agrees better with observations.
The CTM results show that very early chemical ozone loss occurred in December 2002 due to extremely low temperatures and early chlorine activation in the lower stratosphere. Thus, chemical loss in this winter started earlier than in the other two winters studied here. In 2002/2003 the local polar ozone loss in the lower stratosphere was ~40% before the stratospheric final warming. Larger ozone loss occurred in the cold year 1999/2000 which had a persistently cold and stable vortex during most of the winter. For this winter the current model, at a resolution of 2.8° x 2.8°, can reproduce the observed loss of over 70% locally. In the warm and more disturbed winter 2003/2004 the chemical O3 loss was generally much smaller, except above 620K where large losses occurred due to a period of very low minimum temperatures at these altitudes.
Number concentrations of total and non-volatile aerosol particles with size diameters >0.01 μm as well as particle size distributions (0.4–23 μm diameter) were measured in situ in the Arctic lower stratosphere (10–20.5 km altitude). The measurements were obtained during the campaigns European Polar Stratospheric Cloud and Lee Wave Experiment (EUPLEX) and Envisat-Arctic-Validation (EAV). The campaigns were based in Kiruna, Sweden, and took place from January to March 2003. Measurements were conducted onboard the Russian high-altitude research aircraft Geophysica using the low-pressure Condensation Nucleus Counter COPAS (COndensation PArticle Counter System) and a modified FSSP 300 (Forward Scattering Spectrometer Probe). Around 18–20 km altitude typical total particle number concentrations nt range at 10–20 cm−3 (ambient conditions). Correlations with the trace gases nitrous oxide (N2O) and trichlorofluoromethane (CFC-11) are discussed. Inside the polar vortex the total number of particles >0.01 μm increases with potential temperature while N2O is decreasing which indicates a source of particles in the above polar stratosphere or mesosphere. A separate channel of the COPAS instrument measures the fraction of aerosol particles non-volatile at 250°C. Inside the polar vortex a much higher fraction of particles contained non-volatile residues than outside the vortex (~67% inside vortex, ~24% outside vortex). This is most likely due to a strongly increased fraction of meteoric material in the particles which is transported downward from the mesosphere inside the polar vortex. The high fraction of non-volatile residual particles gives therefore experimental evidence for downward transport of mesospheric air inside the polar vortex. It is also shown that the fraction of non-volatile residual particles serves directly as a suitable experimental vortex tracer. Nanometer-sized meteoric smoke particles may also serve as nuclei for the condensation of gaseous sulfuric acid and water in the polar vortex and these additional particles may be responsible for the increase in the observed particle concentration at low N2O. The number concentrations of particles >0.4 μm measured with the FSSP decrease markedly inside the polar vortex with increasing potential temperature, also a consequence of subsidence of air from higher altitudes inside the vortex. Another focus of the analysis was put on the particle measurements in the lowermost stratosphere. For the total particle density relatively high number concentrations of several hundred particles per cm3 at altitudes below ~14 km were observed in several flights. To investigate the origin of these high number concentrations we conducted air mass trajectory calculations and compared the particle measurements with other trace gas observations. The high number concentrations of total particles in the lowermost stratosphere are probably caused by transport of originally tropospheric air from lower latitudes and are potentially influenced by recent particle nucleation.
Balloon-borne measurements of CFC11 (from the DIRAC in situ gas chromatograph and the DESCARTES grab sampler), ClO and O3 were made during the 1999/2000 Arctic winter as part of the SOLVE-THESEO 2000 campaign, based in Kiruna (Sweden). Here we present the CFC11 data from nine flights and compare them first with data from other instruments which flew during the campaign and then with the vertical distributions calculated by the SLIMCAT 3D CTM. We calculate ozone loss inside the Arctic vortex between late January and early March using the relation between CFC11 and O3 measured on the flights. The peak ozone loss (~1200ppbv) occurs in the 440-470K region in early March in reasonable agreement with other published empirical estimates. There is also a good agreement between ozone losses derived from three balloon tracer data sets used here. The magnitude and vertical distribution of the loss derived from the measurements is in good agreement with the loss calculated from SLIMCAT over Kiruna for the same days.
A new version of a digital global map of irrigation areas was developed by combining irrigation statistics for 10 825 sub-national statistical units and geo-spatial information on the location and extent of irrigation schemes. The map shows the percentage of each 5 arc minute by 5 arc minute cell that was equipped for irrigation around the year 2000. It is thus an important data set for global studies related to water and land use. This paper describes the data set and the mapping methodology and gives, for the first time, an estimate of the map quality at the scale of countries, world regions and the globe. Two indicators of map quality were developed for this purpose, and the map was compared to irrigated areas as derived from two remote sensing based global land cover inventories.
Flow velocity in rivers has a major impact on residence time of water and thus on high and low water as well as on water quality. For global scale hydrological modeling only very limited information is available for simulating flow velocity. Based on the Manning-Strickler equation, a simple algorithm to model temporally and spatially variable flow velocity was developed with the objective of improving flow routing in the global hydrological model of Water- GAP. An extensive data set of flow velocity measurements in US rivers was used to test and to validate the algorithm before integrating it into WaterGAP. In this test, flow velocity was calculated based on measured discharge and compared to measured velocity. Results show that flow velocity can be modeled satisfactorily at selected river cross sections. It turned out that it is quite sensitive to river roughness, and the results can be optimized by tuning this parameter. After the validation of the approach, the tested flow velocity algorithm has been implemented into the WaterGAP model. A final validation of its effects on the model results is currently performed.
The Kaon-Spectrometer (KaoS) at the heavy-ion synchrotron (SIS) at the Gesellschaft für Schwerionenforschung (GSI) in Darmstadt has been used to study production and propagation of K+ and K- mesons from Au+Au collisions at a kinetic beam energy of 1.5 AGeV. This energy for K+ mesons is close to the corresponding production threshold in binary nucleon-nucleon collisions and far below for K- mesons. The azimuthal angular distributions of particles as a function of the collision centrality and particle transverse momenta have been measured. The properties of strange mesons are expected to be modified by the in-medium meson-baryon potential. Theoretical calculations show that the superposition of the scalar and vector potentials leads to a small repulsive K+N and a strong attractive K-N potential. Additionally, the interaction of kaons and antikaons with nuclear matter is different. The strangeness conservation law inhibits the absorption probability of K+ mesons as they contain an s-quark. K- mesons, however, interact with nucleons via strangenessexchange (K- + N ->Y + pion, where Y = lambda, sigma). Moreover, the reverse process (pion + Y -> K- + N) is the dominant production mechanism of K- mesons at SIS energies. The azimuthal angular emission patterns of kaons are expected to be sensitive to the in-medium potentials. An enhanced out-of-plane emission of K+ mesons was observed in Au+Au reactions at 1.0 AGeV and 1.5 AGeV, and also in Ni+Ni at 1.93 AGeV. The out-of-plane emission of K+ mesons in Au+Au reactions at 1.0 AGeV was interpreted as a consequence of a repulsive K+N potential in the nuclear medium, however, recent transport calculations show that the emission patterns obtained in Au+Au at 1.5 AGeV and Ni+Ni at 1.93 AGeV are additionally influenced by the re-scattering of kaons. For K- mesons the calculations predict an almost isotropic emission pattern due to the attractive K-N potential which counteracts the absorption of K- mesons in the spectator fragments. In Ni+Ni collisions at 1.93 AGeV the azimuthal distribution of K- mesons has been found to be isotropic. In this case, however, the spectators are rather small and have large relative velocities. In addition, the delay of antikaon emission due to strangenessexchange reaction minimizes the interaction with the spectators. As a consequence the sensitivity of the K- meson emission pattern to the K-N in-medium potential is reduced. In Au+Au collisions we found a dependence of the K- meson azimuthal emission pattern on the transverse momentum. The antikaons registered with pt < 0.5 GeV/c are preferentially emitted in the reaction plane and the particles with pt > 0.5 GeV/c show strong out-of-plane enhancement. The emission patterns of K- can be explained in terms of two competing phenomena: one of them is indeed the influence of the attractive K-N potential, however, the second one originates from the strangeness-exchange process.
Soluble guanylyl cyclase (sGC) is a cytosolic enzyme producing the intracellular messenger cyclic guanosine monophosphate (cGMP) on activation with nitric oxide (NO) which leads to the activation of GMP dependent protein kinases and to vasodilation. NO signaling may be affected by altered expression of sGC subunits, as has been shown in different pathological and physiological conditions and developmental stages. The molecular mechanisms underlying altered sGC expression in these and other conditions have not yet been revealed. Gene expression can also be regulated at the level of mRNA through alterations in translational efficiency and in mRNA stability. HuR (Human R) is a ubiquitously expressed member of the embryonic lethal abnormal vision (ELAV) family of RNA-binding proteins. Among other RNAs, there has been recent evidence that the expression of sGC is subject to post-transcriptional regulation by HuR. It has been shown that chronic hypertension induces changes in HuR expression and activity, which account for decreased sGC expression and activity in the aorta of hypertensive rats. This thesis should study was performed in an effort to provide some insight to the transcriptional and post-transcriptional regulation of sGC expression in a mammal, the rat. We investigated rat sGC alpha-1 transcriptional regulation in rat lung fibroblast (RLF-6) cells. The 3000bp 5' upstream region of the alpha-1 sGC gene was isolated and analyzed for promoter activity by using luciferase reporter constructs- Alpha3000 (with -2794 bp), Alpha1100 (-1092 bp), Alpha350 (-346 bp) and Alpha200 (-200 bp). The promoter activity was the highest in the 200bp construct (about 6-fold higher than Alpha3000) suggesting that this fragment contains all the crucial elements necessary to support basal transcription of the alpha-1 sGC gene. Analysis of the 200 bp of the 5’ UTR of the alpha-1 gene was performed using the MATINSPECTOR V2.2 software for putative transcription factors. The constructs containing the deleted sites for NFY and Sp1 showed a significant decrease in constitutive promoter activity by almost 80% and 60% respectively, implying that these transcription factors are crucial elements in the basal expression of the of sGC alpha-1 subunit. Treatment of RLF-6 cells with genistein 50 microM and mithramycinA 100 nM, known to inhibit the NFY and Sp1 binding to DNA respectively, reflected the same effects. Furthermore the cGMP content of the cells was significantly reduced by both inhibitors, almost completely by genistein, and by about 40 % by mithramycinA. Electrophoretic mobility-shift assay (EMSA) clearly showed the formation of multiple complexes with the biotinylated ODN (decoy oligodeoxynucleotide) probes for NFY and Sp1 when incubated with RLF-6 nuclear extract. A “supershift” observed in the presence of antibodies to the individual transcription factors confirmed that these factors were present in the shifted band, indeed. NFY and Sp1 are instrumental in several physiological and pathophysiological effects mediated by several growth factors in smooth muscle cells. Thus the regulation of the promoter, in response to serum, was also analysed. 10% foetal calf serum led to decreased alpha-1 sGC level as shown by western blots performed with rat aorta. Decreased sGC alpha-1 mRNA expression was observed in RLF-6 cells and cultured rat aortic smooth muscle cells incubated with FCS for 24 hours. This decrease was reflected in the promoter activity in RLF-6 cells using both Alpha3000 and Alpha200 constructs confirming that the regulation took place at promoter level. EMSA performed with nuclear extracts from FCS treated RLF-6 cells led to diminished binding to NFY, but to an enhanced binding to Sp1 site. We concluded that the factors Sp1 and NFY (the sites overlapping) compete for binding, and in the presence of FCS, it is Sp1 that binds stronger, and hence results in diminishing promoter activity. In order to delineate the post-transcriptional regulation of sGC alpha-1 subunit, studies were performed to demonstrate the regulation of expression of the mRNA stabilizing protein HuR. It has been observed that exposure of isolated rat aortic segments to the activator of adenylyl cyclase, forskolin, strongly reduced sGC alpha-1/beta-1 and HuR protein and mRNA expression in a time-dependent and actinomycin D-sensitive fashion. Transcription factor decoy approach proved that the cAMP-induced down-regulation of HuR is mediated by the activation of AP-1. It has been established that HuR stabilises the sGC alpha-1 and beta-1 mRNA. However the pathway underlying this regulation remains unknown. In order to identify the mechanism of this regulation, we looked for HuR interacting proteins employing the yeast two hybrid assay. The enzyme of the polyamine catabolic pathway spermidine/spermine N1-acetyltransferase (SSAT) was found to interact with the hinge region of HuR. This interaction was confirmed by performing immunoprecipitation and GST-pulldown experiments. A direct effect of these proteins on each other’s biological activity was not visible as tested through the SSAT activity assay and HuR gel shift. It might be possible that SSAT-mediated modulation of local polyamine concentrations enhances/reduces HuR activity and sGC expression to affect cell proliferation. In summary, this study represents an analysis of the rat sGC alpha-1 promoter regulation in rat fibroblast cells and identifies NFY and Sp1 as important factors in sGC alpha-1 expression. It also gives first evidence of sGC regulation at the transcriptional level in response to an external stimulus, and proposes the possible mechanism. It also identifies SSAT as a HuR interacting protein. These might have implications in the various pathophysiological conditions where sGC plays an important role.
The generation of O2- by NADPH oxidaes was mainly attributed to immune cells that kill invading bacteria or cancer cells. But importantly, in the past several years, several homologs of the catalytic subunit gp91phox (Nox2) of the phagocytic NADPH oxidase have been identified in non-immune cells and tissues. Superoxide production derived from NADPH oxidaes has been shown to play a role not only in host defense but also in defined signaling cascades mediating growth and apoptosis. The aim of this work was to study the expression and the regulation of the”new” Nox isoforms in rat renal mesangial cells (MC). In particular the following results were achieved. 1) mRNA’s for both Nox1 and Nox4 were detected by RT-PCR. 2) Nox1 mRNA levels were increased upon exposure to basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF) and fetal calf serum (FCS) in a time- and dose-dependent manner. Exposure of MC to bFGF and FCS increased also basal production of reactive oxygen species (ROS) by MC. By contrast, Nox4 mRNA levels were not significantly affected by bFGF treatment, but were markedly down-regulated by PDGF and FCS. 3) To study the regulation of Nox1 on the protein level, an anti-Nox1 antibody was generated and characterized using affinity chromatography. Up-regulation of Nox1 expression by growth factors was confirmed also on the protein level. 4) Based on the already known cDNA sequence for Nox1, the transcriptional start site was determined by the “gene RACE” technique. 2547 bp of the genomic sequence of the 5´-flanking region of the Nox1 gene were cloned and sequenced using the „Genome-Walking“ method. To study the regulation of Nox1 transcription functional Nox1 promoter/luciferase fusions were be established. MC were transiently transfected with different promoter/luciferase constructs and stimulated with growth factors. By measuring luciferase activity it was determined that growth factors induced the Nox1 transcription and that the Nox1 core promoter is sufficient for the activation. 5) By measurement of superoxide radicals and analysis of Nox1 mRNA expression by quantitative RT-PCR (TaqMan) as well as protein level by Western blotting it could be shown that treatment of MC with NO donors inhibited the expression of Nox1 in a time- and dose-dependent manner. Moreover, using activators and inhibitors of the soluble guanylyl cyclase (sGC) it could be shown, that the activation of sGC mediates the effect of NO on Nox1 expression. However, NO had no inhibitory effect on Nox1 promoter activity. Experiments with the inhibitor of transcription, actinomycin D, suggest that NO-mediated regulation of Nox1 is triggered probably via post-transcriptional mechanisms. Nox4 is regulated on the mRNA levels in a similar manner as Nox1. 6) To analyze the sub-cellular localization of the Nox isoforms, coding sequences for Nox1 and Nox4 were fused together with green fluorescent protein into the pEGFP-N1 demonstrated that both isoforms are localized predominantly in the plasma membrane, but also in the perinuclear region and cytoplasm. However, the localization of Nox1 in the plasma membrane was more pronounced. 7) In addition to Nox1 and Nox4, mRNA of the newly identified NOXA1 that is a homolog of the p67phox subunit of NADPH oxidase was detected in MC by RT-PCR.
In large models of neuronal cell death, there is a tight correlation between Cdk5 deregulation and cell-cycle dysfunction. However, pathways that link Cdk5 to the cell cycle during neuronal death are still unclear. We have investigated the molecular events that precede p25/Cdk5-triggered neuronal death using a neuronal cell line that allows inducible p25 expression. In this system, no sign of apoptosis was seen before 24 hours of p25 induction. Thus, at that time, cell-cycle-regulatory proteins were analysed by immunoblotting and some of them showed a significant deregulation. Interestingly, after time-course experiments, the earliest feature correlated with p25 expression was the phosphorylation of the retinoblastoma protein (Rb). Indeed, this phosphorylation was observed 6 hours after p25 induction and was abolished in the presence of a Cdk5 inhibitor, roscovitine, which does not inhibit the usual Rb cyclin-D kinases Cdk4 and Cdk6. Furthermore, analyses of levels and subcellular localization of Cdk-related cyclins did not reveal any change following Cdk5 activation, arguing for a direct effect of Cdk5 activity on Rb protein. This latter result was clearly demonstrated by in vitro kinase assays showing that the p25-Cdk5 complex in our cell system phosphorylates Rb directly without the need for any intermediary kinase activity. Hence, Rb might be an appropriate candidate that connects Cdk5 to cell-cycle deregulation during neuronal cell death.
Introduction: Reactive oxygen species (ROS) have been implicated in neurodegeneration and seem to be involved in the physiology and pathophysiology of several diseases, including normal aging and Alzheimer’s disease (AD). Enhanced ROS production in aging or AD is not restricted to the brain, but can also been seen in several peripheral tissues. The objective of the present study was to evaluate whether the mechanisms involved in the generation of oxidative stress in normal senescence and Alzheimer’s disease are identical or not. Methods: We analysed intracellular basal levels of ROS in lymphocytes from AD patients and healthy young and aged not-demented subjects as well as ROS levels following stimulation with d-ribose and staurosporine in all three groups. ROS levels were measured by flow cytometry using the intracellular fluorescence dye dihydrorhodamine123 (DHR123). Results: Our study shows that AD lymphocytes have increased basal levels of ROS, low susceptibility to ROS stimulation by 2-deoxy-D-ribose (dRib) and an increased response to staurosporine when compared with age-matched controls. Discussion: The data suggest that the defect(s) responsible for enhanced ROS production in AD may involve different or additional biological pathways than those involved in enhanced ROS generation during aging.
Studies in particular of the last decade showed that active neurogenesis continuously takes place in the subventricular zone (SVZ) of the lateral ventricles of the adult rodent brain. Neurogenesis in the SVZ leads to migration of neuroblasts within the rostral migratory stream (RMS) and mature neuron formation mainly in the olfactory bulb (OB). According to present understanding, glial cells with astrocytic properties represent the actual adult neural stem cells. The cell types representing the various cellular transition states leading to the formation of mature neurons as well as the mechanisms controlling adult neurogenesis and neuroblast migration are poorly understood. A previous study from this laboratory demonstrated that the ATP-hydrolyzing enzyme nucleoside triphosphate diphosphohydrolase 2 (NTPDase2) is associated with type B cells, the presumptive neural stem cells. NTPDase2 is a protein of the plasma membrane with its catalytic site facing the extracellular space. It hydrolyzes extracellular nucleoside triphosphates to their respective nucleoside diphosphates. This raises the possibility that the signaling pathway via extracellular nucleotides is involved in the control of adult neurogenesis. Neurons as well as glial cells express several subtypes of receptors (P2 receptors) that are responsive to the nucleotides ATP, ADP, UTP, or UDP. P2X receptors are ATP-gated Na+, K+ and Ca2+ permeable ion channels, P2Y receptors are coupled to trimeric G-proteins. In order to probe for a functional role of nucleotides in adult neurogenesis, the present study referred to an in vitro system (neurospheres). Neurospheres produced from isolates of the mouse SVZ and cultured in the presence of EGF and bFGF expressed the neural stem cell marker nestin and also GFAP, S100β, NTPDase2 and tissue non-specific alkaline phosphatase. Neurospheres generated from the cells of the subventricular zone were multipotenital. This was revealed by immunostaining of differentiated cells with markers for astrocytes, neurons and oligodendrocytes. The presence of ecto-nucleotidase was verified by analyzing the free phosphate released from nucleotides. The tissue non-specific form of alkaline phosphatase was the predominant enzyme. Both NTPDase2 and TNAP could be identified by immunocytochemistry and Western blotting. Hydrolysis was not observed for p-nitrophenyl thymidine monophosphate, a substrate of members of the ectonucleotide pyrophosphatase/phosphodiesterase family (NPP1 to NPP3). Since ecto-nucleotidases control the availability of extracellular nucleotide agonists, neurospheres were studied for the potential expression and functional role of nucleotide receptors. Neurospheres responded to extracellular nucleotides with a transient rise in Ca2+ (ATP = ADP > UTP). The rise in Ca2+ was due to P2Y receptors. The Ca2+ response was unaltered in the absence of extracellular Ca2+ and strongly reduced by thapsigargin, a blocker of internal Ca2+ stores. The P2Y1 antagonist MRS2179 strongly reduced the ATP- or ADP-induced increase in Ca2+, suggesting the involvement of a P2Y1 receptor. In addition, suramin and PPADS, non-selective antagonists for P2 receptors, inhibited most of the Ca2+ response. The agonistic activity of UTP and the lack of response to UDP implied the additional presence of a P2Y2 and/or a P2Y4 receptors and the absence of a functional P2Y6 receptor. RT-PCR experiments demonstrated that neurospheres expressed P2Y1 and P2Y2 receptors but not P2Y4 receptor. That the majority of the Ca2+ response to ATP was mediated via P2Y1 receptors was also confirmed by analysis of P2Y1 knockout mice and by application of the P2Y1 receptor-specific antagonist MRS2179. In addition, agonists of P2Y1 and P2Y2 receptors and low concentrations of adenosine augmented cell proliferation inspite of the presence of mitogenic growth factors. Neurosphere cell proliferation was attenuated after application of MRS2179 and in neurospheres from P2Y1 receptor knockout mice. These results infer a nucleotide receptor-mediated synergism that augments growth factor-mediated cell proliferation. Taken together these results suggest that P2Y-mediated nucleotidergic signalling is involved in neurosphere function and possibly also in adult neurogenesis in situ.
The Na+/proline transporter of E. Coli (PutP) is responsible for the uptake of proline which is subsequently used not only as a carbon and nitrogen source and a constituent of proteins but also as a particularly effective osmoprotectant. However, for a long time there was little known about the single steps in the reaction cycle of this transporter and only few details about its structure-function relationship are available. Aim of the present work was to achieve a deeper understanding about the kinetic properties of the Na+/proline transporter and to get insights into the structure-function relationship of the substrate binding. To answer these questions different techniques were used. By using the novel SSM technique combining the preparation of PutP proteoliposomes it was possible to demonstrate for the first time the electrogenic substrate binding to PutP transporter. Due to rapid solution exchange measurements on the SSM it was additionally possible to obtain time resolved information about the kinetic details of the cytoplasmic substrate binding sites which were not available by previous steady state and equilibrium binding measurements. Pre-steady-state charge translocation was observed after rapid addition of one or both of the cosubstrates Na+ and/or proline to the PutP-WT proteoliposomes adsorbed on the SSM. Thereby it was possible to link the observed electrical signals with the binding activity of PutP. The observed Na+ and/or proline induced charge displacement were assigned to an electrogenic Na+ and/or proline binding process at the cytoplasmic face of the enzyme with a rate constant of k > 50 s-1 proceeding the rate limiting step of the reaction cycle. Furthermore, based on the kinetic analysis of the electrical signals obtained from the measurements of PutP on SSM, the following characteristics of the substrates binding in PutP were deduced: (1) both Na+ and proline can bind individually to the transporter. Under physiological conditions, an ordered binding mechanism prevails; while at sufficiently high concentrations, each substrate can bind in the absence of the other; (2) substrate binding is electrogenic not only for Na+, but also for the uncharged cosubstrate proline. The charge displacement associated with Na+ binding and proline binding is of comparable size and independent of the presence of the respective cosubstrate. In addition, it was concluded that Na+ accesses its binding site through a high-field access channel resulting in a charge translocation, whereas the binding of the electroneutral proline induces a conformation alteration involving the displacement of charged amino acid residue(s) of the protein; (3) Na+ and proline binding sites interact cooperatively with each other by increasing the affinity and/or the speed of binding of the respective cosubstrate; (4) proline binding proceeds in a two step process: low affinity (~ 0.9 mM) electroneutral substrate binding followed by a nearly irreversible electrogenic conformational transition; (5) membrane impermeable PCMBS inhibits both Na+ and proline binding to the inside-out orientated PutP transporter, indicating that rather than selectively blocking a specific binding site, PCMBS probably locks the enzyme in an inactive state. The possible targets for this SH-reagent are cysteines 281 and 344 located close to the cytoplasmic surface of the protein. Beyond it, transient electrical currents of PutP were also observed on the BLM after rapid addition of proline in the presence of Na+. This was possible by combining the conventional BLM technique with high-speed flash-photolysis of caged-proline. Indeed the signals on the BLM indicate the detection of a different underlying reaction process in comparison to the data achieved by the SSM technique. This has paved the way for supplemental information about the reaction cycle since it was possible to assign the flash-photolysis BLM signals to the proline binding step followed by the internalization of Na+ and proline into the liposome. Thereby it was found, that the presence of Na+ is indispensable and the time constant for the process is ~ 63 ms. Moreover, structure-function information about the Na+ and proline binding sites of PutP was obtained by investigating the functionally important amino acid residues Asp55, Gly63 and Asp187 with site-directed mutagenesis and the combined SSM technique. One finding is that the mutated proteins PutP-D55C and PutP-G63C showed no activity on the SSM. Therefore, it can be assumed that either both Asp55 and Gly63 are crucial for the structure of PutP protein, or they are located at or close to the Na+ and proline binding sites. Furthermore, the results obtained from PutP-D187N and PutP-D187C mutants on SSM suggest that Asp187 of PutP is likely to be involved in the Na+ binding at the cytoplasmic side of the backward running carrier. Taken together the results of the present work have substantially broadened the known picture of the Na+/proline transporter PutP thereby several steps of the reaction cycle were elucidated, and moreover, valuable insights into the structure-function relationship of the transporter have become available.
The technique of site-specific fluorescence labelling with Tetramethylrhodaminemaleimide (TMRM) in combination with two electrode voltage-clamp technique (TEVC), an approach that has been named voltage clamp fluorometry (VCF), has been used in this work to study the Na,K-ATPase. The TMRM dye has the ability to attach covalently to cysteine residues and it responds to changes in the hydrophobicity of its local environment. We exploited this property using a construct of the Na-pump in which the native, extracellularly accessible cysteines were removed and cysteine residues were introduced by site-directed mutagenesis in specific positions of the Na-pump. In this way it was possible to detect site-specific conformational rearrangements of the Na-pump in a time-resolved fashion within a native membrane environment. In particular this technique allows to resolve reactions with low electrogenicity that cannot be satisfactorily analyzed with purely electrophysiological techniques and to identify the conformations of the enzyme under specific ionic composition of the measuring buffers. We used VCF to study the influence that several cations like Na+, K+, NMG+, TEA+ and BTEA+ exert on the distribution of the Na,K-ATPase between several enzymatic intermediates and on some of the reactions related to cation transport. To this end we utilized the mutants N790C in the loop M5-M6 and the mutant E307C, T309C, L311C and E312C in the loop M3-M4. From the correspondence of the fluorescence changes with the activation and inhibition of pumping current, by K+ and ouabain respectively, and from the fact that in Na+/Na+ exchange conditions the voltage distribution of charge movement and fluorescence changes evoked by voltage jumps are in reasonable agreement we conclude that through the fluorescence signals measured from these mutants, we can indeed monitor conformational changes linked to transport activity of the enzyme. For the mutants N790 and L311, it was found that the Na+ dependence of the amplitude and kinetics of the fluorescence signal associated with the E1P-E2P transition is in agreement with the prediction of an access channel model describing the regulation of the access of extracellular Na+ to its binding site. In particular for the mutants E307 and T309 it was found that in Na+/Na+ exchange conditions, the conformational change tracked by the fluorescence was much slower than the charge relaxation at hyperpolarized potentials while the kinetics was very similar at depolarized potentials. This implies that at hyperpolarized potentials the conformational change connected to the E1P-E2P transition does not give a large contribution to the electrogenicity of the process which is also consistent with the access channel model. On the mutant N790C it was found that the external pH does not seem to have any effect on the E1P-E2P equilibrium even if it seems to modulate the fluorescence quantum yield of the dye. Fluorescence quenching experiments with iodide and D2O indicate that at hyperpolarized potentials the local environment of the mutant N790C, experiences a small change in the accessibility to water without major changes in the local electrostatic field ...
Sodium proton antiporters are ubiquitous membrane proteins found in the cytoplasmic and organelle membranes of cells of many different origins, including plants, animals and microorganisms. They are involved in cell energetics, and play primary roles in the homeostasis of intracellular pH, cellular Na+ content and cell volume. Adaptation to high salinity and/or extreme pH in plants and bacteria or in human heart muscles requires the action of such Na+/H+ antiporters. NhaA is the essential Na+/H+ antiporter for pH and Na+ homeostasis (at alkaline pH) in Escherichia coli and many other enterobacteria. NhaA is an electrogenic Na+/H+ antiporter that exchanges 2H+ for 1Na+ (or Li+). NhaA shares with many other prokaryotic and eukaryotic antiporters a very strong dependence on pH. In order to achieve three-dimensional structure of NhaA, the previously described NhaA protein preparation was modified: (i) the wild type bacterial strain (TA16) used for homologous over-expression of NhaA was replaced with a delta nhaA strain (RK20). As a result, the purity and homogeneity of the sample was significantly improved; (ii) the previously two-step purification procedure was shortened to a single step affinity chromatography purification; (iii) a wide-range screening of crystallisation conditions, more than 20,000, was performed; (iv) a Seleno-L-methionine (SeMet) NhaA derivative was produced in order to solve the phases during structure determination. In parallel, attempts of production and crystallisation of co-complexes composed of NhaA and antibody fragments have been made. Four different monoclonal antibodies were available against NhaA. Selected antibody fragments were produced and the stability of the complex analysed. Here, the crystal structure of the pH down-regulated secondary transporter NhaA of Escherichia coli is presented at 3.45 Å resolution. A negatively charged ion funnel opens to the cytoplasm and ends in the middle of the membrane at the putative ion-binding site. There, a unique assembly of two pairs of short helices connected by crossed, extended chains creates a balanced electrostatic environment. A possible mechanism is proposed: the binding of charged substrates causes electric imbalance inducing movements, which allow for a rapid alternating access mechanism. This ion exchange machinery is regulated by a conformational change elicited by a pH signal perceived at the cytoplasmic funnel entry. The structure represents a novel fold that provides two major insights: it reveals the structural basis for the mechanism of Na+/H+ exchange and its unique regulation by pH in NhaA and in many other similar antiporters. Furthermore, it is also important for the understanding of the architecture of membrane proteins in general. However, although many aspects of the ion-translocation mechanism and pH regulation are clarified by the NhaA structure, higher resolution structures with Li+ or Na+ bound are required for understanding the ligand binding and the translocation mechanism at the atomic level. The alkaline pH-induced conformation is essential to further understand the pH-control and proton access to the binding site.
In this thesis, we opened the door towards a novel estimation theory for homogeneous vectors and have taken several steps into this new and uncharted territory. Present state of the art for homogeneous estimation problems treats such vectors p 2 Pn as unit vectors embedded in Rn+1 and approximates the unit hypersphere by a tangent plane (which is a n-dimensional real space, thus having the same number of degrees of freedom as Pn). This approach allows to use known and established methods from real space (e.g. the variational approach which leads to the FNS algorithm), but it only works well for small errors and has several drawbacks: • The unit sphere is a two-sheeted covering space of the projective space. Embedding approaches cannot model this fact and therefore can cause a degradation of estimation quality. • Linearization breaks down if distributions are not highly concentrated (e.g. if data configurations approach degenerate situations). • While estimation in tangential planes is possible with little error, the characterization of uncertainties with covariance matrices is much more problematic. Covariance matrices are not suited for modelling axial uncertainties if distributions are not concentrated. Therefore, we linked approaches from directional statistics and estimation theory together. (Homogeneous) TLS estimation could be identified as central model for homogeneous estimation and links to axial statistics were established. In the first chapters, a unified estimation theory for the point data and axial data was developed. In contrast to present approaches, we identified axial data as a specific data model (and not just as directional data with symmetric probability density function); this led to the development of novel terms like axial mean vectors, axial variances and axial expectation values. Like a tunnel which is constructed from both ends simultaneously, we also drilled from the parameter estimation side towards directional/axial statistics in the second part. The presentation of parameter estimation given in this thesis deviates strongly from all known textbooks by presenting homogeneous estimation problems as a distinguished class of problems which calls for different estimation tools. Using the results from the first part, the TLS solution can be interpreted as the weighted anti-mean vector of an axial sample. This link allows to use our results from axial statistics; for instance, the certainty of the anti-mode (i.e. of the TLS solution!) can be described with a weighted Bingham distribution (see (3.91)). While present approaches are only interested in the eigenvector of the some matrix, we can now exploit the whole mean scatter matrix to describe TLS solution and its certainty. Algorithms like FNS, HEIV or renormalization were presented in a common context and linked to each other. One central result is that all iterative homogeneous estimation algorithms essentially minimize a series of evolving Rayleigh coefficients which corresponds to a series of (converging?) cost functions. Statistical optimization is only possible if we clearly identify every step as what it exactly is. For instance, the vague statement “solving Xp ... 0” means nothing but setting ˆp := arg minp pTXp pT p . We identified the most complex scenario for which closed form optimal solutions are possible (in terms of axial statistics: the type-I matrix weighted model). The IETLS approach which is developed in this thesis then solves general type-II matrix weighted problems with an iterative solution of a series of type-I matrix weighted problems. This approach also allows to built converging schemes including robust and/or constrained estimation – in contrast to other approaches which can have severe convergence problems even without such extensions if error levels are not low. Chapter 6 then is another big step forward. We presented the theoretical background of homogeneous estimation by introducing novel concepts like singular vector unbiasedness of random matrices and solved the problem of optimal estimation for correlated data. For instance, these results could be used for better estimation of local image orientation / optical flow (see section 7.2). At the end of this thesis, simulations and experiments for a few computer vision applications were presented; besides orientation estimation, especially the results for robust and constrained estimation for fundamental matrices is impressive. The novel algorithms are applicable for a lot of other applications not presented here, for instance camera calibration, factorization algorithm formulti-view structure from motion, or conic fitting. The fact that this work paved the way for a lot of further research is certainly a good sign.
The N-terminal domain (matrix protein or MA) of a retroviral Gag polyprotein precursor plays a critical role in several stages of the retrovirus life cycle. MA is involved in the effective membrane targeting, assembly and release of the immature viral particles from the infected cell. In order to understand the structural basis of these functions, the full length MA from Moloney Murine Leukemia Virus (MoMuLV) was purified and the solution structure of the MA MoMuLV was determined by means of heteronuclear high-resolution NMR spectroscopy and compared with that of the X-ray diffraction analysis as well as with the structures of several MA proteins from geterologous viruses. Structural features were also obtained from CD spectroscopy, dynamic light scattering, sedimentation velocity, differential scanning calorimetry and other methods. It was found that the MA MoMuLV globular core (residues 8-98) is comprised of 7 well-defined helices (five alpha-helices and two 310 helices), with the general fold typical for MA proteins from other retroviral species. The N-terminus (residues Met1-Leu7) and the C-terminal proline-rich part (residues Pro103-Tyr131) are not structured in solution. Although MA MoMuLV has a low sequence identity compared with other matrix proteins for which the three-dimensional structure is known, it was shown that its overall topology and pattern of secondary structural units is similar to other retroviral matrix proteins. The monomeric state is observed for the correctly folded MA MoMuLV in a variety of external conditions and protein concentrations, indicating that virion assembly starts with the plasma membrane targeting of the nascent Gag precursor. The denaturation of MA MoMuLV is irreversible and is connected with protein aggregation. For Moloney Murine Leukemia Virus (MoMuLV) a proteolytic processing of the R-peptide (last 16 amino acids from the C-terminus of the Envelope protein (Env)) has been described as a second mode of fusion and activation preceding the receptor contact between the viral particle and the cellular membrane. An interaction between the R-peptide and MA MoMuLV has been proposed, since the R-peptide and MA are localized at the inner part of the membrane. Therefore the interaction between 15N labelled purified MA MoMuLV and synthesized R-peptide has been investigated using high-resolution NMR. It was found that in water solution MA MoMuLV and R-peptide do not form a tight complex, but in a mature virion in the presence of membranes or other protein factors it might be possible. In the case of HIV-1 the cytoplasmic part (EnvC) of the Env protein is much longer than in other retroviruses and again as for MoMuLV little is known about the interaction between EnvC and HIV MA. Hence, the full length HIV MA, and the last 150 amino acids from HIV Env have been subcloned with suitable expression vectors, purified and analysed by native gel electrophoresis, a pull down assay and by high resolution NMR for the purpose to detect the complex formation of EnvC and HIV MA. Finally, after all those experiments, it was found that a stable complex is not formed, but a weak interaction between the two proteins can not be excluded.
I derive a general effective theory for hot and/or dense quark matter. After introducing general projection operators for hard and soft quark and gluon degrees of freedom, I explicitly compute the functional integral for the hard quark and gluon modes in the QCD partition function. Upon appropriate choices for the projection operators one recovers various well-known effective theories such as the Hard Thermal Loop/ Hard Dense Loop Effective Theories as well as the High Density Effective Theory by Hong and Schaefer. I then apply the effective theory to cold and dense quark matter and show how it can be utilized to simplify the weak-coupling solution of the color-superconducting gap equation. In general, one considers as relevant quark degrees of freedom those within a thin layer of width 2 Lambda_q around the Fermi surface and as relevant gluon degrees of freedom those with 3-momenta less than Lambda_gl. It turns out that it is necessary to choose Lambda_q << Lambda_gl, i.e., scattering of quarks along the Fermi surface is the dominant process. Moreover, this special choice of the two cutoff parameters Lambda_q and Lambda_gl facilitates the power-counting of the numerous contributions in the gap-equation. In addition, it is demonstrated that both the energy and the momentum dependence of the gap function has to be treated self-consistently in order to determine the imaginary part of the gap function. For quarks close to the Fermi surface the imaginary part is calculated explicitly and shown to be of sub-subleading order in the gap equation.
Background: The flavin in its FMN and FAD forms is a versatile cofactor that is involved in catalysis of most disparate types of biological reactions. These include redox reactions such as dehydrogenations, activation of dioxygen, electron transfer, bioluminescence, blue light reception, photobiochemistry (as in photolyases), redox signaling etc. Recently, hitherto unrecognized types of biological reactions have been uncovered that do not involve redox shuffles, and might involve the reduced form of the flavin as a catalyst. The present work addresses properties of reduced flavin relevant in this context. Results: N(5)-H exchange reactions of the flavin reduced form and its pH dependence were studied using the 15N-NMR-signals of 15N-enriched, reduced flavin in the pH range from 5 to 12. The chemical shifts of the N(3) and N(5) resonances are not affected to a relevant extent in this pH range. This contrasts with the multiplicity of the N(5)-resonance, which strongly depends on pH. It is a doublet between pH 8.45 and 10.25 that coalesces into a singlet at lower and higher pH values. From the line width of the 15N(5) signal the pH-dependent rate of hydrogen exchange was deduced. The multiplicity of the 15N(5) signal and the proton exchange rates are little dependent on the buffer system used. Conclusion: The exchange rates allow an estimation of the pKa value of N(5)-H deprotonation in reduced flavin to be ≥ 20. This value imposes specific constraints for mechanisms of flavoprotein catalysis based on this process. On the other hand the pK ≈ 4 for N(5)-H protonation (to form N(5)+-H2) would be consistent with a role of N(5)-H as a base.
CFSnewsletter is a documentation of past, present and future CFS activities in the fields of research, executive development and events. Printed versions of all issues published since 1997 can be ordered free of charge. To download the latest issues, you need ADOBE Acrobat Reader. Contact: Lut De Moor Phone: +49-(0)69-798-30060 Fax: +49-(0)69-798-30077 media_contact (AT) ifk-cfs.de
G protein-coupled receptors (GPCRs) play regulatory roles in many different physiological processes and they represent one of the most important class of drug targets. However, due to the lack of three-dimensional structures, structure based drug design has not been possible. The major bottleneck in getting three-dimensional crystal structure of GPCRs is to obtain milligram quantities of pure, homogenous and stable protein. Therefore, during my Ph.D. thesis, I focused on expression, characterization and isolation of three GPCRs namely human bradykinin receptor subtype 2 (B2R), human angiotensin II receptor subtype 1 (AT1aR), and human neuromedin U receptor subtype 2 (NmU2R). These receptors were heterologously produced in three different expression systems (i.e. Pichia pastoris, insect cells and mammalian cells), biochemically characterized and subsequently solubilized and purified for structural studies The human bradykinin receptor subtype 2 (B2R) is constitutively expressed in a variety of cells, including endothelial cells, vascular smooth muscle cells and cardiomyocytes. Activation of B2R is important in pathogenesis of inflammation, pain, tissue injury and cardioprotective mechanisms. During this study, recombinant B2R was produced in methylotrophic yeast Pichia pastoris (3.5 pmol/mg), insect cells (10 pmol/mg) and mammalian cells (60 pmol/mg). The recombinant receptor was characterized in terms of [3H] bradykinin binding, G protein coupling, localization, and glycosylation. Subsequently, it was solubilized and purified using affinity chromatography. Homogeneity and stability of purified B2R was monitored by gel filtration analysis. Milligram amounts of pure and stable receptor were obtained from BHK cells and Sf9 cells, which were used for three-dimensional crystallization attempts. The second receptor, which I worked on, is human angiotensin II receptor subtype 1 (AT1aR). AT1aR is distributed in smooth muscle cells, liver, kidney, heart, lung and testis. Activation of AT1aR is implicated in the regulation of blood pressure, hypertension and cardiovascular diseases. Recombinant AT1aR was produced at high levels in Pichia pastoris (167 pmol/mg), while at moderate levels in insect cells (29 pmol/mg) and mammalian cells (32 pmol/mg). The recombinant receptor was characterized in terms of [3H] angiotensin II binding, localization, and glycosylation. Subsequently, the receptor was solubilized and purified using affinity chromatography. Homogeneity and stability of purified AT1aR was monitored by gel filtration analysis. Milligram amounts of pure and stable receptor were obtained from Pichia pastoris, which were used for threedimensional crystallization attempts. In addition to B2R and AT1aR, I also attempted to produce and isolate the human neuromedin U receptor subtype 2 (NmU2R), which was deorphanized recently. It is found in highest abundance in the central nervous system, particularly the medulla oblongata, spinal cord and thalamus. The distribution of this receptor suggests its regulatory role in sensory transmission and modulation. During this study, recombinant NmU2R was produced in Pichia pastoris (6 pmol/mg) and BHK cells (9 pmol/mg). Recombinant receptor was characterized with regard to [125I] NmU binding, localization and glycosylation. Subsequently, the receptor was solubilized and purified using affinity chromatography. Due to its low expression level, further expression optimization is required in order to obtain milligram amounts for structural studies. The long-term goal of this study was to obtain three-dimensional crystal structure of recombinant GPCRs. However, 3-dimensional crystallization of human recombinant membrane proteins still remains a difficult task. On the other hand, recent advances in the solid-state NMR spectroscopy offer ample opportunities to study receptor-ligand systems, provided milligram quantities of purified receptor are available. Therefore, in parallel to 3-dimensional crystallization trials, purified B2R was also used for solid-state NMR analysis in order to investigate the receptor bound conformation of bradykinin. Preliminary results are promising and indicate significant structural changes in bradykinin upon binding to B2R. Further experiments are ongoing and will hopefully result in the structure of receptor bound bradykinin. One of the challenges in GPCR crystallization is the small hydrophilic surface area that is available to make crystal contacts. One possibility to overcome this problem can be the reconstitution of a GPCR complex with an interacting protein for cocrystallization. For this purpose, I coexpressed B2R and AT1aR, which form a stable heterodimer complex, in BHK cells. I could successfully isolate the heterodimer complex by using two-step affinity purification. Unfortunately, this complex was not stable over time and disassociates within three days of purification. However, during coexpression of B2R and AT1aR in BHK cells, I observed that B2R was localized in the plasma membrane in coexpressing cells while it was retained intracellularly when expressed alone. This coexpression of AT1aR with B2R resulted in a four-fold increase in [3H] bradykinin binding sites on the cell surface. In addition, these two receptors were cointernalized in response to their individual specific ligands. Interestingly, colocalization of B2R and AT1aR was also found in human foreskin fibroblasts (which endogenously express both receptors), in line with the possibility that heterodimerization may be required for surface localization of B2R in native tissues as well. This is the first report where surface localization of a peptide GPCR is triggered by a distantly related peptide GPCR. These data support the hypothesis that heterodimerization may be a prerequisite for cell surface localization of some GPCRs. A second approach that I followed to stabilize the purified B2R was to reconstitute the B2R-β-arrestin complex. β-arrestin is a cytosolic protein that participates in agonist mediated desensitization of GPCRs and therefore dampens the cellular responses initiated by the activation of GPCRs. I tried to reconstitute B2R-β-arrestin complex in vitro by mixing purified B2R and purified β-arrestin. But, no interaction of these two proteins was observed in the pull-down assays. However, a C-terminal mutant of B2R (where a part of the C-terminus of the B2R is exchanged with that of the vasopressin receptor) was found to interact with β-arrestin in vitro as revealed by pull-down assays. In conclusion, this work establishes the production, characterization and isolation of three recombinant human GPCRs. Recombinant receptors were produced in milligram amounts and therefore, pave the way for structural analysis. The heterodimer complex of B2R-AT1aR and B2R-β-arrestin complex can be of great help during crystallization. In addition, it was also found for the first time that the surface localization of a peptide GPCR can be triggered by heterodimerization with a distantly related peptide GPCR.
We evaluate the importance of the precautionary saving motive by relying on a direct question about precautionary wealth from the 1995 and 1998 waves of the Survey of Consumer Finances. In this survey, a new question has been designed to elicit the amount of desired precautionary wealth. This allows us to assess the amount of precautionary accumulation and to overcome many of the problems of previous works on this topic. We find that a precautionary saving motive exists and affects virtually every type of household. However, precautionary savings account for only 8 percent of total wealth holdings. Even though this motive does not give rise to large amounts of wealth, particularly for young and middle-age households, it is particularly important for two groups: older households and business owners. Overall, we provide strong evidence that we need to take the precautionary saving motive into account when modeling saving behavior. Klassifizierung: D91, E21, C21
In the classical Dirac equation with strong potentials, called overcritical, a bound state reaches the negative continuum. In QED the presence of a static overcritical external electric field leads to a charged vacuum and indicates spontaneous particle creation when the overcritical field is switched on. The goal of this work is to clarify whether this effect exists, i.e. if it can be uniquely defined and proved, in time-dependent physical processes. Starting from a fundamental level of the theory we check all mathematical and interpretational steps from the algebra of fields to the very effect. In the first, theoretical part of this thesis we introduce the mathematical formulation of the classical and quantized Dirac theory with their most important results. Using this language we define rigorously the notion of spontaneous particle creation in overcritical fields. First, we give a rigorous definition of resonances as poles of the resolvent or the Green's function and show how eigenvalues become resonances under Hamiltonian perturbations. In particular, we consider essential for overcritical potentials perturbation of eigenvalues at the edge of the continuous spectrum. Next, we gather various adiabatic theorems and discuss well-posedness of the scattering in the adiabatic limit. Then, we construct Fock space representations of the field algebra, study their equivalence and give a unitary implementer of all Bogoliubov transformations induced by unitary transformations of the one-particle Hilbert space as well as by the projector (or vacuum vector) changes as long as they lead to unitarily equivalent Fock representations. We implement in Fock space self-adjoint and unitary operators from the one-particle space, discussing the charge, energy, evolution and scattering operators. Then we introduce the notion of particles and several particle interpretations for time-dependent processes with a different Fock space at every instant of time. We study how the charge, energy and number of particles change in consequence of a change of representation or in implemented evolution or scattering processes, what is especially interesting in presence of overcritical potentials. Using this language we define rigorously the notion of spontaneous particle creation. Then we look for physical processes which show the effect of vacuum decay and spontaneous particle creation exclusively due to the overcriticality of the potential. We consider several processes with static as well as suddenly switched on (and off) static overcritical potentials and conclude that they are unsatisfactory for observation of the spontaneous particle creation. Next, we consider properties of general time-dependent scattering processes with continuous switch on (and off) of an overcritical potential and show that they also fail to produce stable signatures of the particle creation due to overcriticality. Further, we study and successfully define the spontaneous particle creation in adiabatic processes, where the spontaneous antiparticle is created as a result of a resonance (wave packet) decay in the negative continuum. Unfortunately, they lead to physically questionable pair production as the adiabatic limit is approached. Finally, we consider extension of these ideas to non-adiabatic processes involving overcritical potentials and argue that they are the best candidate for showing the spontaneous pair creation in physical processes. Demanding creation of the spontaneous antiparticle in the state corresponding to the overcritical resonance rather quick than slow processes should be considered, with a possibly long frozen overcritical period. In the second part of this thesis we concentrate on a class of spherically symmetric square well potentials with a time-dependent depth. First, we solve the Dirac equation and analyze the structure and behaviour of bound states and appearance of overcriticality. Then, by analytic continuation we find and discuss the behaviour of resonances in overcritical potentials. Next, we derive and solve numerically (introducing a non-uniform continuum discretization for a consistent treatment of narrow peaks) a system of differential equations (coupled channel equations) to calculate particle and antiparticle production spectra for various time-dependent processes including sudden, quick, slow switch on and off of a sub- and overcritical potentials. We discuss in detail how and under which conditions an overcritical resonance decays during the evolution giving rise to the spontaneous production of an antiparticle. We compare the antiparticle production spectrum with the shape of the resonance in the overcritical potential. We study processes, where the overcritical potentials are switched on at different speed and are possibly frozen in the overcritical phase. We prove, in agreement with conclusions of the theoretical part, that the peak (wave packet) in the negative continuum representing a dived bound state partially follows the moving resonance and partially decays at every stage of its evolution. This continuous decay is more intensive in slow processes, while in quick processes the wave packet more precisely follows the resonance. In the adiabatic limit, the whole decay occurs already at the edge of the continuum, resulting in production of antiparticles with vanishing momentum. In contrast, in quick switch on processes with delay in the overcritical phase, the spectrum of the created antiparticles agrees best with the shape of the resonance. Finally, we address the question how much information about the time-dependent potential can be reconstructed from the scattering data, represented by the particle production spectrum. We propose a simple approximation method (master equation) basing on an exponential, decoherent decay of time-dependent resonances for prediction of particle creation spectra and obtain a good agreement with the results of full numerical calculations. Additionally, we discuss various sources of errors introduced by the numerical discretization, find estimations for them and prove convergence of the numerical schemes.
This thesis is devoted to the study of Micro Structured Electrode (MSE) sustained discharges. Innovative approaches in this work are i) the implementation of MSE arrays for high-pressure plasma generation and ii) the use of diode laser atomic absorption spectroscopy for investigating sub-millimetric discharges. By means of MSE arrays the discharge gap is scaled down to the sub-millimetric range and accordingly the working pressure could be increased up to atmospheric. It should be underlined that besides the ease of use, since expensive vacuum equipment is not required, high-pressure discharges offer also a high density of active species. A MSE consists of holes, regularly distributed in a composite sheet made of two metal layers separated by an insulator. The electrodes and insulator thickness and the diameter of the holes are in the 100 micrometer range. Based on these microstructures stable non-filamentary DC discharges are generated in noble gases and gas mixtures at pressures up to 1000 mbar. The MSE sustained discharge can be considered as a normal glow discharge whereby the excitation and ionization efficiency is increased by the specific electrode configuration (hollow cathode geometry). Large area high-pressure plasma can be achieved by parallel operation of a large number of microdischarges. Parallel operation of up to 200 microdischarges without individual ballast was proven for pressures up to 300 mbar. Furthermore, arrays of resistively decoupled microdischarges were operated up to atmospheric pressure. Spectral investigations have revealed the presence of highly energetic electrons (20 eV), a large density of atoms in metastable states (1013 cm-3) and a high electron density (1015 cm-3). Although the plasma confined inside the hole of the MSE may reach gas temperatures up to 1000 K, the ambient gas temperature immediately above the microstructure exceeds only slightly the room temperature. The reactivity of the MSE sustained discharge was demonstrated in respect to waste gas decomposition and surface treatment. The MSE arrays are providing a non-equilibrium high-pressure plasma, which is very promising for surface processing, plasma chemistry and generation of UV radiation.
We present a detailed study of chemical freeze-out in p-p, C-C, Si-Si and Pb-Pb collisions at beam momenta of 158A GeV as well as Pb-Pb collisions at beam momenta of 20A, 30A, 40A and 80A GeV. By analyzing hadronic multiplicities within the statistical hadronization model, we have studied the parameters of the source as a function of the number of the participating nucleons and the beam energy. We observe a nice smooth behaviour of temperature, baryon chemical potential and strangeness under-saturation parameter as a function of energy and nucleus size. Interpolating formulas are provided which allow to predict the chemical freeze-out parameters in central collisions at centre-of-mass energies > 4.5 GeV and for any colliding ions. Specific discrepancies between data and model emerge in particle ratios in Pb-Pb collisions at SPS between 20A and 40A GeV of beam energy which cannot be accounted for in the considered model schemes.
One possible approach to study systematically the influence of the deformation regime on the geometry of geological structures like folds and boudins is analogue modelling. For a complete understanding of the resulting structures, consideration of the third dimension is required. This PhD study deals with scaled analogue modelling under constriction and plane-strain conditions to improve our knowledge of folding and boudinage of lower crustal rocks in space and time. Plasticine is an appropriate analogue material for rocks in the lower crust. Therefore, this material was used for the experiments. The macroscopic behaviour of most types of plasticine is quite similar to rocks undergoing strain-rate softening and strain hardening regardless of the different microscopic aspects of deformation. Therefore, if one is aware that the stress exponent and viscosity increase with increasing strain, the original plasticine types used with stress exponents ranging from 5.8 to 8.0 are adequate for modelling geologic structures. The same holds for plasticine/oil mixtures. Thus, plasticine and plasticine/oil mixtures can be used to model the viscous flow of different rock types in the lower crust. If climb-accommodated dislocation creep and associated steady-state flow is assumed for the natural rocks, the plasticine/oil mixtures should be used, which flow under steady-state conditions. Three different experimental studies of plane-strain coaxial deformation of stiff layers, with viscosity η2 and stress exponent n2, embedded in a weak matrix, with viscosity η1 and stress exponent n1, have been carried out. The undeformed samples (matrix plus layer) were cubes with an edge length of 12 cm. All experimental runs have been carried out at T = 25 ± 1°C and varying strain rates ė, ranging from 7.9 x 10 high -6 s high -1 to 1.7 x 10 high -2 s high -1, until a finite longitudinal strain of 30% – 40% was achieved. The first experimental study improved the understanding about the evolution of folds and boudins when the layer is oriented perpendicular to the Y-axis of the finite strain ellipsoid. The rock analogues used were Beck’s green plasticine (matrix) and Beck’s black plasticine (competent layer), both of which are strain-rate softening modelling materials with stress exponent n = ca. 8. The effective viscosity η of the matrix plasticine was changed by adding different amounts of oil to the original plasticine. At a strain rate ė of 10 high -3 s high -1 and a finite strain e of 10%, the effective viscosity of the matrix ranges from 1.2 x 10 high 6 to 7.2 x 10 high 6 Pa s. The effective viscosity of the competent layer has been determined as 4.2 x 10 high 7 Pa s. If the viscosity ratio is large (> ca. 20) and the initial thickness of the competent layer is small, both folds and boudins develop simultaneously. Although the growth rate of the folds seems to be higher than the growth rate of the boudins, the wavelength of both structures is approximately the same as is suggested by analytical solutions. A further unexpected, but characteristic, aspect of the deformed competent layer is a significant increase in thickness, which can be used to distinguish plane-strain folds and boudins from constrictional folds and boudins. In the second experimental study, the impact of varying strain rates on growing folds and boudins under plane strain have been investigated. The strain rates used range from 7.9 x 10 high -6 s high -1 to 1.7 x 10 high -2 s high -1. The stiff layer and matrix consist of non-linear viscous Kolb grey and Beck’s green plasticine, respectively, both of which are strain-rate softening modelling materials with power law exponents (n) and apparent viscosities (η) ranging from 6.5 to 7.9 and 8.5 x 10 high 6 to 7.2 x 10 high 6 Pa s, respectively. The effective viscosity (η) of the matrix plasticine was partly modified by adding oil to the original plasticine. At the strain rates used in the experiments the viscosity ratio between layer and matrix ranges between 3 and 10. Different runs have been carried out where the layer was oriented perpendicular to the principal strain axes (X>Y>Z). The results suggest a considerable influence of the strain rate on the geometry of the deformed stiff layer including its thickness. This holds for every type of layer orientation (S ┴ X, S ┴ Y, S ┴ Z). If the stiff layer is oriented perpendicular to the short axis Z of the finite strain ellipsoid, the number of the resulting boudins and the thickness of the stiff layer increase, whereas the length of boudins decreases with increasing strain rate. If the stiff layer is oriented perpendicular to the long axis, X, of the finite strain ellipsoid, enlargement of the strain rate results in increasing wavelength of folds, whereas the number of folds and the degree of thickening of the stiff layer decreased. If the stiff layer is oriented perpendicular to the intermediate Y-axis of the finite strain ellipsoid enlargement of the strain rate results in a decreasing number of boudins and folds associated with increasing wavelengths of both structures. The wavelength of folds is approximately half of the boudins wavelength. This is true for the case where folds and boudins develop simultaneously (S ┴ Y) and for cases where both structures develop independently (folds at S ┴ X and boudins at S ┴ Z). In the third experimental study, scaled analogue experiments have been carried out to demonstrate the growth of plane-strain folds and boudins through space and time. Previous 3D-studies are based only on finite deformation structures. Their results can therefore not be used to prove if both structures grew simultaneously or in sequence. Plane strain acted on a single stiff layer that was embedded in a weak matrix, with the layer oriented perpendicular to the intermediate Y-axis of the finite strain ellipsoid. Two different experimental runs have been carried out using computer tomography (CT) to analyse the results. The first run was carried out without interruption. During the second run, the deformation was stopped in each case at longitudinal strain increments of 10%. Every experiment was carried out at a temperature T of 25°C and a strain rate, ė, of ca. 4 x 10 high -3 s high -1 until a finite longitudinal strain of 40% was achieved with a viscosity contrast m of 18.6 between the non-linear viscous layer (Kolb brown plasticine) and the matrix (Beck’s green plasticine with 150 ml oil kg high -1). The apparent viscosity, η, and the stress exponent, n, for the layer at a strain rate ė = ca. 10 high -3 s high -1 and a finite strain e = 10% are 2.23 x 10 high 7 Pa s and n = 5.8 and for the matrix 1.2 x 10 high 6 Pa s and 10.5. These new data that result from incremental analogue modelling corroborate previous suggestions that folds and boudins are coeval structures in cases of plane-strain coaxial deformation with the stiff layer oriented perpendicular to the intermediate Y-axis of the finite strain ellipsoid. They will be of interest for all workers who are dealing with plane-strain boudins and folds, where the fold axes are parallel to the major axis (X) of the finite strain ellipsoid. As has been demonstrated by the first experimental study, coeval folding and boudinage under plane strain, with S ┴ Y, are associated with a significant increase in the thickness of the competent layer. The latter phenomenon does not occur in other cases of simultaneous folding and boudinage, such as bulk pure constriction. To study the impact of layer thickness on the geometry of folds and boudins under pure constriction, we carried out additional experiments using different types of plasticine for a stiff layer and a weaker matrix to model folding and boudinaging under pure constriction, with the initially planar layer oriented parallel to the Xaxis of the finite strain ellipsoid. The stiff layer and matrix consist of non-linear viscous Kolb brown and Beck’s green plasticine, respectively, both of which are strain-rate softening modelling materials. Six runs have been carried out using thicknesses of the stiff layer of 1, 2, 4, 6, 8 and 10 ± 0.2 mm. All experimental runs were carried out at a temperature T of 30 ± 2°C and a strain rate, ė, of ca. 1.1 x 10 high -4 s high -1 until a finite longitudinal strain of 40% was achieved with a viscosity contrast m of 3.1 between the stiff layer (Kolb brown plasticine) and the matrix (Beck’s green plasticine). The apparent viscosity, η, and the stress exponent, n, for the layer at a strain rate ė = ca. 10 high -3 s high -1 and a finite strain e = 10% are 2.23 x 10 high 7 Pa s and n = 5.8 and for the matrix 7.2 x 10 high 6 Pa s and 7.9. Our results suggest a considerable influence of the initial thickness of the stiff layer on the geometry of the deformed stiff layer. There is no evidence for folding in XY=XZ-sections if the initial thickness of the competent layer is larger than ca. 8 mm. If the initial thickness of the competent layer is set at ca. 10 ± 0.2 mm, both folds and boudins develop simultaneously. However, the growth rate of the boudins seems to be higher than the growth rate of the folds. A further expected, but characteristic, aspect of the deformed competent layer is no change in thickness of the competent layer, which can be used to distinguish plane-strain folds and boudins from constrictional folds and boudins. The model results are important for the analysis and interpretation of deformation structures in rheologically stratified rocks undergoing dislocation creep under bulk constriction. Tectonic settings where constrictional folds and boudins may develop simultaneously are stems of salt diapirs, subduction zones or thermal plumes. To make (paleo) viscosimetric statements possible, the rheological data of the different plasticine types were related to the geometrical data. When comparing the normalized dominant wavelength Wd obtained from the deformed layer of the models with the theoretical dominant wavelength (Ld) calculated using the Smith equation (1977, 1979), the latter probably also holds when folding and boudinage develop simultaneously (S ┴ Y) and when boudins develop independently (S ┴ Z), but can obviously not be applied at very low viscosity ratios as is indicated by the low-strain-rate experiments.
Acute myeloid leukemia (AML) is characterized by the accumulation of a large number of abnormal, immature blast cells. Recently, histone deacetylase inhibitors (HDIs) received considerable interest on the ground of their ability to overcome the differentiation block in these leukemic blasts regardless of the primary genetic alteration, an effect achieved either alone or in combination with differentiating agents, such as all-trans retinoic acid (t-RA). Valproic acid (VPA), a potent HDI, is now under clinical evaluation owing to its potent differentiation effect on transformed hematopoietic progenitor cells and leukemic blasts from AML patients. Conversely, in a clinical study by Bug et al., the favorable effects of the combination treatment with t-RA/VPA in advanced acute myeloid leukemia patients were reported to be most likely due to an enhancement of nonleukemic myelopoiesis and the suppression of malignant hematopoiesis rather than enforced differentiation of the leukemic cells. Based on the hypothesis that VPA influences normal hematopoiesis, the effect of chromatin modeling through VPA on HSCs was investigated with respect to differentiation, proliferation as well as self-renewal in the present study. It has been shown that valproic acid increases both proliferation and self-renewal of HSC. It accelerates cell cycle progression of HSC accompanied by a down-regulation of p21cip-1/waf-1. Furthermore, valproic acid inhibits GSK3B by phosphorylation on Ser9 accompanied by an activation of the Wnt signaling pathway as well as by an up-regulation of HoxB4, a target gene of Wnt signaling. Both are known to directly stimulate the proliferation of HSC and to expand the HSC pool. To sum up, valproic acid, a potent histone deacetylase inhibitor known to induce differentiation and/or apoptosis in leukemic blasts, stimulates the proliferation and self-renewal of hematopoietic stem cells. Therefore, the data reported in this study suggest to reconsider the role of histone deacetylase inhibitors from a differentiation inducer to a coadjuvant factor for increasing the response to conventional therapy in acute myeloid leukemia.
Haematopoietic stem cells (HSCs) are regarded as the prime target for gene therapy of inherited and acquired disorders of the blood system, e.g. X-linked chronic granulomatous disease (X-CGD). The major reason for this is that HSCs posses the ability to self renew as well as the potential to differentiate into all lineage-specific cell types. However, the need to reach and to maintain sufficient therapeutic levels of genetically modified stem cells and their progeny after gene delivery still presents major challenges for current HSC gene therapy approaches. In particular, one of the main limitations for most genetic defects is the lack of a selective growth advantage of gene-modified cells after engraftment. In vitro and in vivo methods have been developed that focus on either positive or negative selection of HSCs. An artificial selection advantage can be conferred to transduced HSCs by incorporating a selection marker in addition to the therapeutic transgene. In the present study, two novel strategies for positive selection of murine gp91phox gene-modified haematopoietic stem cells were developed and tested, bearing in mind that with selective growth advantage, the possibility of uncontrolled proliferation arises. The first strategy to be investigated was based on the homeobox transcription factor HOXB4, which plays an important role in the control of haematopoietic stem cell proliferation and differentiation. Overexpression of a retroviral bicistronic construct containing the therapeutic gene gp91phox and HOXB4 in murine primary bone marrow cells led to a significant 3–4-fold expansion of transduced cells ex vivo. The numbers of transgene-expressing cells increased 2–3-fold after 2 weeks cultivation under cytokine stimulation. Furthermore, the clonogenic progenitor cell assay (CFU assay) demonstrated that the number of colony-forming cells had increased to levels 2-fold higher than those of mock-transduced cells after 1 week of culture, thereby augmenting the presence of a significant number of stem/progenitor cells in the selected cell population. However, in our experiments, HOXB4-overexpressing murine HSCs did not show any repopulating advantage in transplanted recipient mice over control construct-transduced HSCs. These results indicate that selective expansion of gp91phox gene-modified HSCs can be induced by the HOXB4 transcription factor ex vivo but not in vivo. This is possibly dependent on HOXB4 expression levels, which are too low in vivo to achieve selection. The second strategy made use of a chemically inducible dimerizer system consisting of the therapeutic gene gp91phox and a fusion protein, containing sequences from a growth factor receptor signalling domain (epidermal growth factor receptor, EGFR, or prolactin receptor, PrlR) and the drug binding protein FKBP12, as the selection cassette. This strategy aimed to allow inducible selection that could be easily switched off. The activity of these fusion proteins is controlled through the small molecular dimerizer AP20187. Transduction of BaF/3 cells with lentiviral vectors expressing the EGFR construct induced proliferation and led to complete selection within 18 days (99%). However, removing AP20187 could not turn off proliferation. This construct is, therefore, not suitable as a selection cassette for the expansion of gene-modified HSCs due to its oncogenic potential. Transduction of the construct containing the intracellular domain of PrlR caused significant selective expansion of AP20187-treated BaF/3 cells. Following expression in cells, the fusion protein, which lacks membrane-anchoring sequences, mainly localized to the cytoplasm. Evidence was found to indicate that activated STAT5 might be responsible for this effect. Upon expression of the prolactin construct, phosphorylation of STAT5 and its DNA-binding activity to a ß-casein promoter sequence was strongly increased. Importantly, the induced proliferation was reversible after removal of AP20187. Transduced Sca1+ bone marrow cells obtained from C57BL/6-CD45.1 mice could be expanded about 20–100-fold ex vivo in the presence of AP20187 and mSCF without losing progenitor cell features and the capability to contribute to all lineages of the haematopoietic system. To exclude oncogenic outgrowth of one single clone, the polyclonality of selected cells was proven by ligation-mediated PCR (LM-PCR) analysis. In mouse transplantation experiments, ex vivo-expanded cells repopulated the bone marrow of lethally irradiated mice suggesting that the ex vivo expansion took place at the level of haematopoietic stem and/or progenitor cells. Genomic gp91phox sequences were detected in the bone marrow, spleen and peripheral blood cells of transplanted animals, indicating that gp91phox-containing cells most likely contributed to the reconstitution of haematopoiesis in these mice.
The illusion of apparent motion can be induced when visual stimuli are successively presented at different locations. It has been shown in previous studies that motion-sensitive regions in extrastriate cortex are relevant for the processing of apparent motion, but it is unclear whether primary visual cortex (V1) is also involved in the representation of the illusory motion path. We investigated, in human subjects, apparent-motion-related activity in patches of V1 representing locations along the path of illusory stimulus motion using functional magnetic resonance imaging. Here we show that apparent motion caused a blood-oxygenation-level-dependent response along the V1 representations of the apparent-motion path, including regions that were not directly activated by the apparent-motion-inducing stimuli. This response was unaltered when participants had to perform an attention-demanding task that diverted their attention away from the stimulus. With a bistable motion quartet, we confirmed that the activity was related to the conscious perception of movement. Our data suggest that V1 is part of the network that represents the illusory path of apparent motion. The activation in V1 can be explained either by lateral interactions within V1 or by feedback mechanisms from higher visual areas, especially the motion-sensitive human MT/V5 complex.
Prostaglandin E2 is the major prostaglandin involved in colorectal carcinogenesis. The biosynthesis of prostaglandin E2 is accomplished by several terminal prostaglandin E synthases through catalytical conversion of the cyclooxygenase product prostaglandin H2. Among the known terminal prostaglandin E synthases, microsomal prostaglandin E synthase type 1 and type 2 were found to be overexpressed in colorectal cancer, however the role and regulation of these enzymes in this tumor entity are yet not fully understood. Here we report that the cyclopentenone prostaglandins 15-deoxy-D12,14-prostaglandin J2 and prostaglandin A2, which have been shown to modulate cell growth and neoplasia, selectively down-regulate microsomal prostaglandin E synthase type 2 mRNA and protein expression in the human colorectal carcinoma cell lines Caco-2 and HCT 116. This effect appeared to be PPARgamma independent and was not found to require G-protein-coupled receptor activation. Instead, inhibition of microsomal prostaglandin E synthase type 2 by cyclopentenone prostaglandins may be mediated by covalent binding of the cyclopentenone ring to cysteine residues on signalling molecules or via a redox-dependent mechanism. Inhibition of microsomal prostaglandin E synthase type 2 was subsequently followed by decreased prostaglandin E synthase activity, which in turn contributed at least in part to the anti-proliferative action of cyclopentenone prostaglandins in HCT 116 cells. Collectively, these data unravel a novel mechanism for the growth-inhibitory effects of cyclopentenone prostaglandins and expose microsomal prostaglandin E synthase type 2 as a new potential target for pharmacological intervention in the treatment of colorectal cancer.