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The transporter associated with antigen processing (TAP) plays a pivotal role in the adaptive immune response against virus-infected or malignantly transformed cells. As member of the ABC transporter family, TAP hydrolyzes ATP to energize the transport of antigenic peptides from the cytosol into the lumen of the endoplasmic reticulum. TAP forms a heterodimeric complex composed of TAP1 and TAP2 (ABCB2/3). Both subunits contain a hydrophobic transmembrane domain and a hydrophilic nucleotide-binding domain. The aim of this work was to study the ATP hydrolysis event of the TAP complex and gain further insights into the mechanism of peptide transport process. To analyze ATP hydrolysis of each subunit I developed a method of trapping 8- azido-nucleotides to TAP in the presence of phosphate transition state analogs followed by photocross-linking, immunoprecipitation, and high-resolution SDS-PAGE. Strikingly, trapping of both TAP subunits by beryllium fluoride is peptide-specific. The peptide concentration required for half-maximal trapping is identical for TAP1 and TAP2 and directly correlates with the peptide-binding affinity. Only background levels of trapping were observed for low affinity peptides or in the presence of the herpes simplex viral protein ICP47, which specifically blocks peptide binding to TAP. Importantly, the peptideinduced trapped state is reached after ATP hydrolysis and not in a backward reaction of ADP binding and trapping. In the trapped state, TAP can neither bind nor exchange nucleotides, whereas peptide binding is not affected. In summary, these data support the model that peptide binding induces a conformation that triggers ATP hydrolysis in both subunits of the TAP complex within the catalytic cycle. The role of the ABC signature motif (C-loop) on the functional non-equivalence of the NBDs was investigated. The C-loops of TAP transporter contain a canonical C-loop (LSGGQ) for TAP1 and a degenerated ABC signature motif (LAAGQ) for TAP2. Mutation of the leucine or glycine (LSGGQ) in TAP1 fully abolished peptide transport. TAP complexes with equivalent mutations in TAP2 showed however still residual peptide transport activity. To elucidate the origin of the asymmetry of the NBDs of TAP, we further examined TAP complexes with exchanged C-loops. Strikingly, the chimera with two canonical C-loops showed the highest transport rate whereas the chimera with two degenerated C-loops had the lowest transport rate, demonstrating that the ABC signature motifs control the peptide transport efficiency. All single-site mutants and chimeras showed similar activities in peptide or ATP binding, implying that these mutations affect the ATPase activity of TAP. In addition, these results prove that the serine of the C-loop is not essential for TAP function, but rather coordinates, together with other residues of the C-loop, the ATP hydrolysis in both nucleotide-binding sites. To study the coupling between the ATP binding/hydrolysis and the peptide binding, the putative catalytic bases of the TAP complex were mutated to generate the so-called EQ mutants. The mutations did not influence the peptide-binding ability. Dimerization of the NBDs of EQ mutants upon ATP binding does not alter the peptide binding property. At 27°C, both ATP and ADP could induce the loss of peptide-binding ability (Bmax) only in the variants bearing a mutated TAP2. Further studies are required to deduce at which stage in the catalytic cycle the peptide-binding site is affected. In addition, mutation of the putative catalytic base of both subunits showed a magnesium-dependent peptide transport activity, demonstrating these mutants did not abolish the ATP hydrolysis. Thus, the function of this acidic residue as the catalytic base is not likely to be universe for all ABC transporters.
This study focuses upon a detailed description and analysis of the phonetic structures of Paiwan, an aboriginal language spoken in Taiwan, with around 53,000 speakers, Paiwan, a member of the Austronesian language family, is not typologically related to the other languages such as Mandarin and Taiwanese spoken in its geographically contiguous districts, Earlier work on phonological features of Paiwan (Chang, 1999; Tseng, 2003) sought an account in terms of segments and isolated facts about reduplication and stress, without accounting for the possible roles of phrase-level and sentence-Ievel prosodic structures, Government Teaching Material (1993) listed 25 consonants and 4 vowels, without any description of phonetic features and phonological rules, Chang's (2000) reference grammar included 22 consonants and 4 vowels, with a very brief description of 5 phonological rules on single words, Regional diversity and 25 consonants have been mentioned in Pulaluyan's (2002) teaching material; however, no description of phonological rules was found in his material.
This paper analyzes banks' choice between lending to firms individually and sharing lending with other banks, when firms and banks are subject to moral hazard and monitoring is essential. Multiple-bank lending is optimal whenever the benefit of greater diversification in terms of higher monitoring dominates the costs of free-riding and duplication of efforts. The model predicts a greater use of multiple-bank lending when banks are small relative to investment projects, firms are less profitable, and poor financial integration, regulation and inefficient judicial systems increase monitoring costs. These results are consistent with empirical observations concerning small business lending and loan syndication. JEL Klassifikation: D82; G21; G32.
We take a simple time-series approach to modeling and forecasting daily average temperature in U.S. cities, and we inquire systematically as to whether it may prove useful from the vantage point of participants in the weather derivatives market. The answer is, perhaps surprisingly, yes. Time-series modeling reveals conditional mean dynamics, and crucially, strong conditional variance dynamics, in daily average temperature, and it reveals sharp differences between the distribution of temperature and the distribution of temperature surprises. As we argue, it also holds promise for producing the long-horizon predictive densities crucial for pricing weather derivatives, so that additional inquiry into time-series weather forecasting methods will likely prove useful in weather derivatives contexts.
The research performed in the DeepThought project aims at demonstrating the potential of deep linguistic processing if combined with shallow methods for robustness. Classical information retrieval is extended by high precision concept indexing and relation detection. On the basis of this approach, the feasibility of three ambitious applications will be demonstrated, namely: precise information extraction for business intelligence; email response management for customer relationship management; creativity support for document production and collective brainstorming. Common to these applications, and the basis for their development is the XML-based, RMRS-enabled core architecture framework that will be described in detail in this paper. The framework is not limited to the applications envisaged in the DeepThought project, but can also be employed e.g. to generate and make use of XML standoff annotation of documents and linguistic corpora, and in general for a wide range of NLP-based applications and research purposes.
In April 2003 I commented on the European Commission’s Action Plan on a More Coherent European Contract Law [COM(2003) 68 final] and the Green Paper on the Modernisation of the 1980 Rome Convention [COM(2002) 654 final].1 While the main argument of that paper, i.e. the common neglect of the inherent interrelation between both the further harmonisation of substantive contract law by directives or through an optional European Civil Code on the one hand and the modernisation of conflict rules for consumer contracts in Art. 5 Rome Convention on the other hand, remain pressing issues, and as the German Law Journal continues its efforts in offering timely and critical analysis on consumer law issues,2 there is a variety of recent developments worth noting.
In the early Nineties the Hague Conference on International Private Law on initiative of the United States started negotiations on a Convention on the Recognition and Enforcement of Foreign Judgments in Civil and Commercial Matters (the "Hague Convention"). In October 1999 the Special Commission on duty presented a preliminary text, which was drafted quite closely to the European Convention on Jurisdiction and Enforcement of Judgments in Civil and Commercial Matters (the "Brussels Convention"). The latter was concluded between the then 6 Member States of the EEC in Brussels in 1968 and amended several times on occasion of the entry of new Member States. In 2000, after the Treaty of Amsterdam altered the legal basis for judicial co-operation in civil matters in Europe, it was transformed into an EC Regulation (the "Brussels I Regulation"). The 1999 draft of the Hague Convention was heavily criticized by the USA and other states for its European approach of a double convention, regulating not only the recognition and enforcement of judgments, but at the same time the extent of and the limits to jurisdiction to adjudicate in international cases. During a diplomatic conference in June 2001 a second draft was presented which contained alternative versions of several articles and thus resembled more the existing dissent than a draft convention would. Difficulties to reach a consensus remained, especially with regard to activity based jurisdiction, intellectual property, consumer rights and employee rights. In addition, the appropriateness of the whole draft was questioned in light of the problems posed by the de-territorialization of relevant conduct through the advent of the Internet. In April 2002 it was decided to continue negotiations on an informal level on the basis of a nucleus approach. The core consensus as identified by a working group, however, was not very broad. The experts involved came to the conclusion that the project should be limited to choice of court agreements. In March 2004 a draft was presented which sets out its aims as follows: "The objective of the Convention is to make exclusive choice of court agreements as effective as possible in the context of international business. The hope is that the Convention will do for choice of court agreements what the New York Convention of 1958 has done for arbitration agreements." In April 2004 the Special Commission of the Hague Conference adopted a Draft "Convention on Exclusive Choice of Court Agreements", which according to its Art. 2 No. 1 a) is not applicable to choice of court agreements, to which a natural person acting primarily for personal, family or household purposes (a consumer) is a party". The broader project of a global judgments convention thus seems to be abandoned, or at least to be postponed for an unlimited time period. There are - of course - several reasons why the Hague Judgments project failed. Samuel Baumgartner has described an important one as the "Justizkonflikt" between the United States and Europe or, more specifically Germany. Within the context of the general topic of this conference, that is (international) jurisdiction for human rights, in the remainder of this presentation I shall elaborate on the socio-cultural aspects of the impartiality of judgments and their enforcement on a global scale.
Semi-permanent quadrats, located in the South and Central Western Slopes botanical regions of New South Wales, were assessed to indicate suitable periods of the year to conduct surveys of botanical diversity. The quadrats were located in woodland communities with a generally herbaceous understorey, and subject to a wide range of domestic stock grazing intensities. In the mid to western South Western Slopes (SWS) the greatest number of species was generally recorded in an October survey. The main exception was in degraded areas (low species diversity, high proportion of annual weed species), where similar results were recorded in September and October. In the cooler and wetter eastern SWS a relatively high proportion of species were recorded in October to early December surveys. However, when compared to species totals compiled from multiple assessments in all seasons, or from August to November, a single optimal survey usually recorded only 60–75% of the plant species at a site. Surveys in mid to late summer, autumn and early winter usually recorded less than 50% of the plant species present. The results reflect the prevailing Mediterranean-type climate, and that the ground layer vegetation (primarily comprised of annuals and herbaceous perennials) dominates the species diversity.
Information literacy is a mosaic of attitudes, understandings, capabilities and knowledge about which there are three myths. The first myth is that it is about the ability to use ICTs to access a wealth of information. The second is that students entering higher education are information literate because student centred, resource based, and ICT focused learning are now pervasive in secondary education. The third myth is that information literacy development can be addressed by library-centric generic approaches. This paper addresses those myths and emphasises the need for information literacy to be recognised as the critical whole of education and societal issue, fundamental to an information-enabled and better world. In formal education, information literacy can only be developed by infusion into curriculum design, pedagogies, and assessment.
We perform a study of the possible existence of hybrid stars with color superconducting quark cores using a specific hadronic model in a combination with an NJL-type quark model. It is shown that the constituent mass of the non-strange quarks in vacuum is a very important parameter that controls the beginning of the hadron–quark phase transition. At relatively small values of the mass, the first quark phase that appears is the two-flavor color superconducting (2SC) phase which, at larger densities, is replaced by the color-flavor locked (CFL) phase. At large values of the mass, on the other hand, the phase transition goes from the hadronic phase directly into the CFL phase avoiding the 2SC phase. It appears, however, that the only stable hybrid stars obtained are those with the 2SC quark cores.
Since the description of sepsis by Schottmüller in 1914, the amount on knowledge available on sepsis and its underlying pathophysiology has substantially increased. Epidemiologic examinations of abdominal septic shock patients show the potential for high risk posed by and the extensive therapy situation in the intensive care unit (ICU) (5). Unfortunately, until now it has not been possible to significantly reduce the mortality rate of septic shock, which is as high as 50-60% worldwide, although PROWESS' results (1) are encouraging. This paper summarizes the main results of the MEDAN project and their medical impacts. Several aspects are already published, see the references. The heterogeneity of patient groups and the variations in therapy strategies is seen as one of the main problems for sepsis trials. In the MEDAN multi-center study of 71 intensive care units in Germany, a group of 382 patients made up exclusively of abdominal septic shock patients who met the consensus criteria for septic shock (3) was analysed. For use within scores or stand-alone experiments variables are often studied as isolated variables, not as a multidimensional whole, e.g. a recent study takes a look at the role thrombocytes play (15). To avoid this limitation, our study compares several established scores (SOFA, APACHE II, SAPS II, MODS) by a multi-dimensional neuronal network analysis. For outcome prediction the data of 382 patients was analysed by using most of the commonly documented vital parameters and doses of medicine (metric variables). Data was collected in German hospitals from 1998 to 2001. The 382 handwritten patient records were transferred to an electronic database giving the amount of 2.5 million data entries. The metric data contained in the database is composed of daily measurements and doses of medicine. We used range and plausibility checks to allow no faulty data in the electronic database. 187 of the 382 patients are deceased (49 %).
In bioinformatics, biochemical signal pathways can be modeled by many differential equations. It is still an open problem how to fit the huge amount of parameters of the equations to the available data. Here, the approach of systematically obtaining the most appropriate model and learning its parameters is extremely interesting. One of the most often used approaches for model selection is to choose the least complex model which “fits the needs”. For noisy measurements, the model which has the smallest mean squared error of the observed data results in a model which fits too accurately to the data – it is overfitting. Such a model will perform good on the training data, but worse on unknown data. This paper propose as model selection criterion the least complex description of the observed data by the model, the minimum description length. For the small, but important example of inflammation modeling the performance of the approach is evaluated. Keywords: biochemical pathways, differential equations, septic shock, parameter estimation, overfitting, minimum description length.
Data driven automatic model selection and parameter adaptation – a case study for septic shock
(2004)
In bioinformatics, biochemical pathways can be modeled by many differential equations. It is still an open problem how to fit the huge amount of parameters of the equations to the available data. Here, the approach of systematically learning the parameters is necessary. This paper propose as model selection criterion the least complex description of the observed data by the model, the minimum description length. For the small, but important example of inflammation modeling the performance of the approach is evaluated.
In bioinformatics, biochemical pathways can be modeled by many differential equations. It is still an open problem how to fit the huge amount of parameters of the equations to the available data. Here, the approach of systematically learning the parameters is necessary. In this paper, for the small, important example of inflammation modeling a network is constructed and different learning algorithms are proposed. It turned out that due to the nonlinear dynamics evolutionary approaches are necessary to fit the parameters for sparse, given data. Keywords: model parameter adaption, septic shock. coupled differential equations, genetic algorithm.
We investigate transverse hadron spectra from relativistic nucleus-nucleus collisions which reflect important aspects of the dynamics - such as the generation of pressure - in the hot and dense zone formed in the early phase of the reaction. Our analysis is performed within two independent transport approaches (HSD and UrQMD) that are based on quark, diquark, string and hadronic degrees of freedom. Both transport models show their reliability for elementary pp as well as light-ion (C+C, Si+Si) reactions. However, for central Au+Au (Pb+Pb) collisions at bombarding energies above ~ 5 A.GeV the measured K+- transverse mass spectra have a larger inverse slope parameter than expected from the calculation. Thus the pressure generated by hadronic interactions in the transport models above ~ 5 A.GeV is lower than observed in the experimental data. This finding shows that the additional pressure - as expected from lattice QCD calculations at finite quark chemical potential and temperature - is generated by strong partonic interactions in the early phase of central Au+Au (Pb+Pb) collisions.
We investigate hadron production and transverse hadron spectra in nucleus-nucleus collisions from 2 A·GeV to 21.3 A·TeV within two independent transport approaches (UrQMD and HSD) based on quark, diquark, string and hadronic degrees of freedom. The enhancement of pion production in central Au+Au (Pb+Pb) collisions relative to scaled pp collisions (the ’kink’) is described well by both approaches without involving a phase transition. However, the maximum in the K+ p+ ratio at 20 to 30 A·GeV (the ’horn’) is missed by ~ 40%. Also, at energies above ~5 A·GeV, the measured K± mT-spectra have a larger inverse slope than expected from the models. Thus the pressure generated by hadronic interactions in the transport models at high energies is too low. This finding suggests that the additional pressure - as expected from lattice QCD at finite quark chemical potential and temperature - might be generated by strong interactions in the early pre-hadronic/partonic phase of central heavy-ion collisions. Finally, we discuss the emergence of density perturbations in a first-order phase transition and why they might affect relative hadron multiplicities, collective flow, and hadron mean-free paths at decoupling. A minimum in the collective flow v2 excitation function was discovered experimentally at 40 A·GeV - such a behavior has been predicted long ago as signature for a first order phase transition.
We investigate hadron production as well as transverse hadron spectra in nucleus-nucleus collisions from 2 A.GeV to 21.3 A.TeV within two independent transport approaches (UrQMD and HSD) that are based on quark, diquark, string and hadronic degrees of freedom. The comparison to experimental data demonstrates that both approaches agree quite well with each other and with the experimental data on hadron production. The enhancement of pion production in central Au+Au (Pb+Pb) collisions relative to scaled pp collisions (the 'kink') is well described by both approaches without involving any phase transition. However, the maximum in the K+/Pi+ ratio at 20 to 30 A.GeV (the 'horn') is missed by ~ 40%. A comparison to the transverse mass spectra from pp and C+C (or Si+Si) reactions shows the reliability of the transport models for light systems. For central Au+Au (Pb+Pb) collisions at bombarding energies above ~ 5 A.GeV, however, the measured K +/- m-theta-spectra have a larger inverse slope parameter than expected from the calculations. The approximately constant slope of K+/-spectra at SPS (the 'step') is not reproduced either. Thus the pressure generated by hadronic interactions in the transport models above ~ 5 A.GeV is lower than observed in the experimental data. This finding suggests that the additional pressure - as expected from lattice QCD calculations at finite quark chemical potential and temperature - might be generated by strong interactions in the early pre-hadronic/partonic phase of central Au+Au (Pb+Pb) collisions.
This paper provides an in-depth analysis of the properties of popular tests for the existence and the sign of the market price of volatility risk. These tests are frequently based on the fact that for some option pricing models under continuous hedging the sign of the market price of volatility risk coincides with the sign of the mean hedging error. Empirically, however, these tests suffer from both discretization error and model mis-specification. We show that these two problems may cause the test to be either no longer able to detect additional priced risk factors or to be unable to identify the sign of their market prices of risk correctly. Our analysis is performed for the model of Black and Scholes (1973) (BS) and the stochastic volatility (SV) model of Heston (1993). In the model of BS, the expected hedging error for a discrete hedge is positive, leading to the wrong conclusion that the stock is not the only priced risk factor. In the model of Heston, the expected hedging error for a hedge in discrete time is positive when the true market price of volatility risk is zero, leading to the wrong conclusion that the market price of volatility risk is positive. If we further introduce model mis-specification by using the BS delta in a Heston world we find that the mean hedging error also depends on the slope of the implied volatility curve and on the equity risk premium. Under parameter scenarios which are similar to those reported in many empirical studies the test statistics tend to be biased upwards. The test often does not detect negative volatility risk premia, or it signals a positive risk premium when it is truly zero. The properties of this test furthermore strongly depend on the location of current volatility relative to its long-term mean, and on the degree of moneyness of the option. As a consequence tests reported in the literature may suffer from the problem that in a time-series framework the researcher cannot draw the hedging errors from the same distribution repeatedly. This implies that there is no guarantee that the empirically computed t-statistic has the assumed distribution. JEL: G12, G13 Keywords: Stochastic Volatility, Volatility Risk Premium, Discretization Error, Model Error
Tests for the existence and the sign of the volatility risk premium are often based on expected option hedging errors. When the hedge is performed under the ideal conditions of continuous trading and correct model specification, the sign of the premium is the same as the sign of the mean hedging error for a large class of stochastic volatility option pricing models. We show, however, that the problems of discrete trading and model mis-specification, which are necessarily present in any empirical study, may cause the standard test to yield unreliable results.
When options are traded, one can use their prices and price changes to draw inference about the set of risk factors and their risk premia. We analyze tests for the existence and the sign of the market prices of jump risk that are based on option hedging errors. We derive a closed-form solution for the option hedging error and its expectation in a stochastic jump model under continuous trading and correct model specification. Jump risk is structurally different from, e.g., stochastic volatility: there is one market price of risk for each jump size (and not just \emph{the} market price of jump risk). Thus, the expected hedging error cannot identify the exact structure of the compensation for jump risk. Furthermore, we derive closed form solutions for the expected option hedging error under discrete trading and model mis-specification. Compared to the ideal case, the sign of the expected hedging error can change, so that empirical tests based on simplifying assumptions about trading frequency and the model may lead to incorrect conclusions.
Tractable hedging - an implementation of robust hedging strategies : [This Version: March 30, 2004]
(2004)
This paper provides a theoretical and numerical analysis of robust hedging strategies in diffusion–type models including stochastic volatility models. A robust hedging strategy avoids any losses as long as the realised volatility stays within a given interval. We focus on the effects of restricting the set of admissible strategies to tractable strategies which are defined as the sum over Gaussian strategies. Although a trivial Gaussian hedge is either not robust or prohibitively expensive, this is not the case for the cheapest tractable robust hedge which consists of two Gaussian hedges for one long and one short position in convex claims which have to be chosen optimally.
This paper deals with the superhedging of derivatives and with the corresponding price bounds. A static superhedge results in trivial and fully nonparametric price bounds, which can be tightened if there exists a cheaper superhedge in the class of dynamic trading strategies. We focus on European path-independent claims and show under which conditions such an improvement is possible. For a stochastic volatility model with unbounded volatility, we show that a static superhedge is always optimal, and that, additionally, there may be infinitely many dynamic superhedges with the same initial capital. The trivial price bounds are thus the tightest ones. In a model with stochastic jumps or non-negative stochastic interest rates either a static or a dynamic superhedge is optimal. Finally, in a model with unbounded short rates, only a static superhedge is possible.
We extend the important idea of range-based volatility estimation to the multivariate case. In particular, we propose a range-based covariance estimator that is motivated by financial economic considerations (the absence of arbitrage), in addition to statistical considerations. We show that, unlike other univariate and multivariate volatility estimators, the range-based estimator is highly efficient yet robust to market microstructure noise arising from bid-ask bounce and asynchronous trading. Finally, we provide an empirical example illustrating the value of the high-frequency sample path information contained in the range-based estimates in a multivariate GARCH framework.
Hartmann and his Prague friends, whether German-Gentile or German-Jewish, rallied enthusiastically to the cause of what at first was a reawakening of suppressed Bohemic cultural nationalism and a move towards across-fertilisation of the two main lingual cultures (Czech/German) andthe three main ethnicities (Czech/German/Jewish) of the country. They soon saw themselves as a "Jungböhmische Bewegung" to correspond to Young Germany. The Prague writer Rudolf Glaser founded a literary journal called 'Ost und West' for the express purpose of bringing together German and Slavic literary impulses under the Goethean motto: "Orient und Occident sind nicht mehr zu trennen". With Bohemia as the bridge, 'Ost und West' published German translations from all the Slavic languages including Pushkin and Gogol, contributions by German writers sympathetic to the cause of emerging nations like Heinrich Laube, Ferdinand Freiligrath, Ernst Willkomm, but above all the Prague circle of Young Bohemians like Alfred Meissner, Isidor Heller, Uffo Horn, Gustav Karpeles and Ignatz Kuranda. Also Hartmann made his literary debut in the journal with a love poem entitled "Der Drahtbinder", and featuring a subtitle which was in keeping with the spirit of the times: "nach einem slavischen Lied".
We point out that during the supernova II type explosion the thermodynamical conditions of stellar matter between the protoneutron star and the shock front correspond to the nuclear liquid–gas coexistence region, which can be investigated in nuclear multifragmentation reactions. We have demonstrated, that neutron-rich hot heavy nuclei can be produced in this region. The production of these nuclei may influence dynamics of the explosion and contribute to the synthesis of heavy elements.
Determination of the structure of complex I of Yarrowia lipolytica by single particle analysis
(2004)
Komplex I enthält ein Flavinmononukleotid sowie mindestens acht Eisen- Schwefel Zentren als redoxaktive Cofaktoren. Da ein wesentlicher Teil des mitochondrialen Genoms für Untereinheiten von Komplex I codiert, betrifft eine Vielzahl von mitochondrialen Erkrankungen diesen Enzymkomplex.
Komplex I wurde bisher aus Mitochondrien, Chloroplasten und Bakterien isoliert. Die Minimalform von Komplex I wird in Bakterien gefunden, wo er aus 14 (bzw 13 im Falle einer Genfusion) Untereinheiten besteht und eine Masse von etwa 550 kDa aufweist. Generell werden sieben hydrophile und sieben hydrophobe Untereinheiten mit über 50 vorhergesagten Transmembranhelices gefunden. Im Komplex I aus Eukaryoten wurde eine grössere Anzahl zusätzlicher, akzessorischer Untereinheiten nachgewiesen. Hier werden die sieben hydrophoben Untereinheiten vom mitochondrialen Genom codiert, während alle anderen Untereinheiten kerncodiert sind und in das Mitochondrium importiert werden müssen.
Die obligat aerobe Hefe Yarrowia lipolytica wurde als Modellsystem zur Untersuchung von eukaryotischem Komplex I etabliert. Die bisher am besten untersuchte Hefe Saccharomyces cerevisiae enthält keinen Komplex I. Hier wird die Oxidation von NADH durch eine andere Klasse von sogenannten alternativen NADH Dehydrogenasen durchgeführt. Auch Y. lipolytica enthält ein solches alternatives Enzym, das allerdings mit seiner Substratbindungsstelle zur Aussenseite der inneren Mitochondrienmembran orientiert ist. Durch molekularbiologische Manipulation konnte eine interne Version dieses Enzymes exprimiert werden, wodurch es möglich ist, letale Defekte in Komplex I Deletionsmutanten zu kompensieren. Mittlerweile wurden alle Voraussetzungen geschaffen, um kerncodierte Untereinheiten von Komplex I aus Y. lipolytica gezielt genetisch zu verändern. Die Proteinreinigung wird durch die Verwendung einer auf einem His-tag basierenden Affinitätsreinigung erheblich erleichtert...
Recent syntactic theory has highlighted the importance of peripheral constructions such as the comparative correlative construction. This construction involves a pair of filler-gap constructions with unusual properties. The first is a subordinate clause and the second a main clause. The construction has a number of related constructions. A version of HPSG, which assumes hierarchies of phrase types, can provide satisfactory analyses both for the comparative correlative constructions and for the related constructions. The two clauses in the comparative-correlative construction can be analysed as non-standard head-filler phrases differing from standard headfiller phrases in certain respects. The construction as a whole can be analyzed as a non-standard head-adjunct phrase, in which the head and the phrase have different categories.
The production of strange pentaquark states (e.g., Theta baryons and Ξ−− states) in hadronic interactions within a Gribov–Regge approach is explored. In this approach the Θ+(1540) and the Ξ are produced by disintegration of remnants formed by the exchange of pomerons between the two protons. We predict the rapidity and transverse momentum distributions as well as the 4π multiplicity of the Θ+, Ξ−−, Ξ−, Ξ0 and Ξ+ for s=17 GeV (SPS) and 200 GeV (RHIC). For both energies more than 10−3 Θ+ and more than 10−5 Ξ per pp event should be observed by the present experiments.
Pathologic data indicate that human cytomegalovirus (HCMV) infection might be associated with the pathogenesis of several human malignancies. However, no definitive evidence of a causal link between HCMV infection and cancer dissemination has been established to date. This study describes the modulation of the invasive behavior of NCAM-expressing tumor cell lines by HCMV. Neuroblastoma (NB) cells, persistently infected with the HCMV strain AD169 (UKF-NB-4AD169 and MHH-NB-11AD169), were added to endothelial cell monolayers and adhesion and penetration kinetics were measured. The 140- and 180-kDa isoforms of the adhesion receptor NCAM were evaluated by flow cytometry, Western blot, and reverse transcriptionpolymerase chain reaction (RT-PCR). The relevance of NCAM for tumor cell binding was proven by treating NB with NCAM antisense oligonucleotides or NCAM transfection. HCMV infection profoundly increased the number of adherent and penetrated NB, compared to controls. Surface expression of NCAM was significantly lower on UKF-NB-4AD169 and MHH-NB-11AD169, compared to mock-infected cells. Western-blot and RT-PCR demonstrated reduced protein and RNA levels of the 140- and 180-kDa isoform. An inverse correlation between NCAM expression and adhesion capacity of NB has been shown by antisense and transfection experiments. We conclude that HCMV infection leads to downregulation of NCAM receptors, which is associated with enhanced tumor cell invasiveness.
Speakers have a wide range of noncanonical syntactic options that allow them to mark the information status of the various elements within a proposition. The correlation between a construction and constraints on information status, however, is not arbitrary; there are broad, consistent, and predictive generalizations that can be made about the information-packaging functions served by preposing, postposing, and argument-reversing constructions. Specifically, preposed constituents are constrained to represent discourse-old information, postposed constituents are constrained to represent information that is either discourse-new or hearer-new, and argument-reversing constructions require that the information represented by the preposed constituent be at least as familiar as that represented by the postposed constituent (Birner & Ward 1998). The status of inferable information (Clark 1977; Prince 1981), however, is problematic; a study of corpus data shows that such information can be preposed in an inversion or a preposing (hence must be discourse-old), yet can also be postposed in constructions requiring hearer-new information (hence must be hearer-new). This information status – discourse-old yet hearer-new – is assumed by Prince (1992) to be non-occurring on the grounds that what has been evoked in the discourse should be known to the hearer. I resolve this difficulty by arguing for a reinterpretation of the term 'discourse-old' as applying not only to information that has been explicitly evoked in the prior discourse, but rather to any information that provides a salient inferential link to the prior discourse. Extending Prince’s notion in this manner allows us to account for the distribution of noncanonically positioned peripheral constituents in a principled and unified way.
Even though tourism has been recognised as an important field for transnational research today, there are few attempts to place tourism in the context of transnational theories or to think about transnationalism from the perspective of tourists. I argue that in researching tourist practices one can add important aspects to transnational approaches. The prerequisites of mobility and interaction for example are the features chosen by backpackers to describe what their Round-The-World-Trip is about. A form of tourism is adopted, or created, that itself confronts many aspects of globalisation: First of all there is the immense dynamic that is involved. Backpackers try to cover as many places and experiences as possible, travelling at high speed. They adopt all kinds of touristic experiences ranging from beach to adventure to culture tourism. They don't focus on a specific area or country but travel the world. They cross national borders perpetually. Additionally they form a transnational network in which they interact with strangers of similar backgrounds (other backpackers, tourist professionals). This network helps them interacting with people from different backgrounds (the socalled hosts or locals). Considering my research Backpackers forge a certain identity from these transnational practices which I want to name globedentity. Globedentity expresses a type of identity construction that not only refers to the individual (I) but reflects the world (globe) in this identity. This globedentity is not fixed but is perpetually re-created and re-defined. It also embraces the increasing popular awareness of globalisation which backpackers, coming from highly educated middle class backgrounds, in particular have identified with. Due to the constant awareness of the latest global social, cultural and economic developments in these educated milieus they know exactly which tools to use to become successful parts of their societies.
In hindsight, the debate about presupposition following Frege’s discovery that the referential function of names and definite descriptions depended on the fulfillment of an existence and a uniqueness condition was curiously limited for a very long time. On the one hand, it was only in the 1960s that linguists began to take an interest and showed that presupposition was an allpervasive phenomenon far beyond this philosophers’ pet definite descriptions. And on the other hand, and this is our real concern, it is now only too obvious that the uniqueness condition is too restrictive to be applicable to the general case. An utterance of “The cat is on the mat” should not imply that there is only one cat and one mat in the whole world. The obvious move is to limit the uniqueness condition to some notion of utterance context.
Configuration, simulation and visualization of simple biochemical reaction-diffusion systems in 3D
(2004)
Background In biological systems, molecules of different species diffuse within the reaction compartments and interact with each other, ultimately giving rise to such complex structures like living cells. In order to investigate the formation of subcellular structures and patterns (e.g. signal transduction) or spatial effects in metabolic processes, it would be helpful to use simulations of such reaction-diffusion systems. Pattern formation has been extensively studied in two dimensions. However, the extension to three-dimensional reaction-diffusion systems poses some challenges to the visualization of the processes being simulated. Scope of the Thesis The aim of this thesis is the specification and development of algorithms and methods for the three-dimensional configuration, simulation and visualization of biochemical reaction-diffusion systems consisting of a small number of molecules and reactions. After an initial review of existing literature about 2D/3D reaction-diffusion systems, a 3D simulation algorithm (PDE solver), based on an existing 2D-simulation algorithm for reaction-diffusion systems written by Prof. Herbert Sauro, has to be developed. In a succeeding step, this algorithm has to be optimized for high performance. A prototypic 3D configuration tool for the initial state of the system has to be developed. This basic tool should enable the user to define and store the location of molecules, membranes and channels within the reaction space of user-defined size. A suitable data structure has to be defined for the representation of the reaction space. The main focus of this thesis is the specification and prototypic implementation of a suitable reaction space visualization component for the display of the simulation results. In particular, the possibility of 3D visualization during course of the simulation has to be investigated. During the development phase, the quality and usability of the visualizations has to be evaluated in user tests. The simulation, configuration and visualization prototypes should be compliant with the Systems Biology Workbench to ensure compatibility with software from other authors. The thesis is carried out in close cooperation with Prof. Herbert Sauro at the Keck Graduate Institute, Claremont, CA, USA. Due to this international cooperation the thesis will be written in English.
[Abstract] Occurrence of hepatitis B virus (HBV) reactivation following kidney transplantation
(2004)
This paper evaluates the effects of Public Sponsored Training in East Germany in the context of reiterated treatments. Selection bias based on observed characteristics is corrected for by applying kernel matching based on the propensity score. We control for further selection and the presence of Ashenfelter's Dip before the program with conditional difference-in-differences estimators. Training as a first treatment shows insignificant effects on the transition rates. The effect of program sequences and the incremental effect of a second program on the reemployment probability are insignificant. However, the incremental effect on the probability to remain employed is slightly positive. JEL - Klassifikation: H43 , C23 , J6 , J64 , C14
While the sortal constraints associated with Japanese numeral classifiers are wellstudied, less attention has been paid to the details of their syntax. We describe an analysis implemented within a broadcoverage HPSG that handles an intricate set of numeral classifier construction types and compositionally relates each to an appropriate semantic representation, using Minimal Recursion Semantics.
We investigated patterns of bryophyte species richness and composition in two forest types of Colombian Amazonia, non-flooded tierra firme forest and floodplain forest of the Caquetá River. A total of 109 bryophyte species were recorded from 14 0.2 ha plots. Bryophyte life forms and habitats were analyzed, including the canopy and epiphylls. Bryophyte species did not show significant differences between landscapes but mosses and liverworts were different and with opposite responses balancing the overall richness. Independence test showed differences in both life form and habitat use distribution between the two forest types with more fan and mat bryophytes species in the floodplains, and more epiphytic liverworts in the tierra firme forest. Correspondence analysis showed differences in the bryophyte species assemblage between the two forest types where they may be responding to the higher humidity provided by the flooding. Despite of, the environmental differences detected, epiphyll species assemblages were not strongly affected. Apparently, epiphyll habitat is stressful enough to hide the environmental differences between the flooded and Tierra firme forests.
Two epiphyllous Lejeuneaceae, Cololejeunea surinamensis and Drepanolejeunea polyrhiza, previously known from Amazonian Brazil, are recorded for the first time in Colombia. They were found as epiphylls on understory shrubs in the middle Caquetá area in Colombian Amazonia. Cololejeunea surinamensis was found in the Tierra Firme forests and D. polyrhiza was found in the floodplains of the Caquetá River.
Angophora inopina is a vulnerable tree species occurring principally in Wyong and Lake Macquarie local government areas on the Central Coast, with disjunct populations as far north as Bulahdelah on the North Coast of NSW. The largest and most intact stands occur within the Wyee-Morisset areas although even here significant fragmentation is evident. North of Toronto, there are small and scattered residual populations as far as Barnsley near West Wallsend in Lake Macquarie. A total area of occupied habitat of approximately 1500 ha is estimated.
Cluster analysis of floristic information showed that Angophora inopina occurs within three broad habitat types within the Central Coast bioregion, centred mainly on the Gorokan, Doyalson and Wyong soil landscapes. Hybrid forms of the species also occur on the Cockle Creek landscape in northern Lake Macquarie. Most stands are evident within open woodland/ forest vegetation where Eucalyptus haemastoma, Corymbia gummifera, and Eucalyptus capitellata dominate with Angophora inopina. Other populations occur in wet heath, and swamp woodland environments where sedge species are characteristic.
Conservation of Angophora inopina will be most effectively and efficiently achieved if ecological processes that operate across the landscape are maintained. Processes such as fragmentation, altered fire regimes or invasion of habitat by exotic species must be managed in the long-term. These are all significant threats to this species, and will best be effectively managed in the larger remnants in a landscape approach. Such threats are generally associated with urban and agricultural expansion in the area, and these are therefore the most pressing issues to be managed.
Werakata National Park (32° 50 S, 151° 25 E), near Cessnock in the Hunter Valley of New South Wales, conserves 2145 ha of mostly open forest vegetation, which was formerly widespread in the lower Hunter Valley. Six vegetation communities are delineated; Lower Hunter Spotted Gum – Ironbark Forest occupies most of the Park. All communities present are considered to be poorly conserved in the region and Werakata plays a critical role in the protection of these vegetation types. Two vegetation communities, Kurri Sand Swamp Woodland and Hunter Lowlands Redgum Forest, are listed as Endangered Ecological Communities under the NSW Threatened Species Conservation Act 1995, while others may warrant future listing. Considerable variation in the floristic composition of the Kurri Sand Swamp Woodland is apparent in the area and the implications are discussed. Populations of four vulnerable plant taxa — Callistemon linearifolius, Eucalyptus parramattensis subsp. decadens, Eucalyptus glaucina, Grevillea parviflora subsp. parviflora, and two rare plant taxa — Grevillea montana, Macrozamia flexuosa, together with several other regionally significant species occur within Werakata.
Recommendations are made on the conservation of plant taxa and vegetation communities in the Cessnock area, and on general reserve management. It is suggested that further areas be added to the reserve to consolidate and expand upon that which is already contained, particularly in regard to threatened species, and endangered and poorly conserved ecological communities.
Fluctuations of charged particle number are studied in the canonical ensemble. In the infinite volume limit the fluctuations in the canonical ensemble are different from the fluctuations in the grand canonical one. Thus, the well-known equivalence of both ensembles for the average quantities does not extend for the fluctuations. In view of a possible relevance of the results for the analysis of fluctuations in nuclear collisions at high energies, a role of the limited kinematical acceptance is studied.
This article proposes a semantics of directional expressions in Norwegian and German, regarded as VP modifiers. The analysis uses Minimal Recursion Semantics, as an integrated part of Matrix-based HPSG grammars. Directional expressions are analyzed as modifying an individual, the 'mover'. Context dependent directionals like here receive a decomposed analysis. Telicity values reflecting various types of directional and locative expressions are computed.
We present a detailed study of chemical freeze-out in nucleus-nucleus collisions at beam energies of 11.6, 30, 40, 80 and 158A GeV. By analyzing hadronic multiplicities within the statistical hadronization approach, we have studied the strangeness production as a function of centre of mass energy and of the parameters of the source. We have tested and compared different versions of the statistical model, with special emphasis on possible explanations of the observed strangeness hadronic phase space under-saturation. We show that, in this energy range, the use of hadron yields at midrapidity instead of in full phase space artificially enhances strangeness production and could lead to incorrect conclusions as far as the occurrence of full chemical equilibrium is concerned. In addition to the basic model with an extra strange quark non-equilibrium parameter, we have tested three more schemes: a two-component model superimposing hadrons coming out of single nucleon-nucleon interactions to those emerging from large fireballs at equilibrium, a model with local strangeness neutrality and a model with strange and light quark non-equilibrium parameters. The behaviour of the source parameters as a function of colliding system and collision energy is studied. The description of strangeness production entails a non-monotonic energy dependence of strangeness saturation parameter gamma_S with a maximum around 30A GeV. We also present predictions of the production rates of still unmeasured hadrons including the newly discovered Theta^+(1540) pentaquark baryon.
Within the tradition of Categorial Grammar, so-called 'non-constituent' coordination ('argument cluster' coordination and 'right node raising') has been analyzed in terms of the coordination of nonstandard constituents produced by the operations of type raising and composition. This highly successful research has expanded the domain of data that modern analyses of coordination must take into account. Recent HPSG work by Yatabe (2002) and Crysmann (2003) provides an interesting alternative approach to this problem in terms of the coordination of familiar, but 'elliptical' constituents. We argue that this approach is empirically superior to the Categorial Grammar analysis, both in terms of empirical coverage and cross-linguistic predictions. We reassess the relevant English data in small but important ways, and develop our own ellipsis analysis, building on Yatabe's and Crysmann's insights.
P-O bond destabilization accelerates phosphoenzyme hydrolysis of sarcoplasmic reticulum Ca2+-ATPase
(2004)
The phosphate group of the ADP-insensitive phosphoenzyme (E2-P) of sarcoplasmic reticulum Ca2+-ATPase (SERCA1a) was studied with infrared spectroscopy to understand the high hydrolysis rate of E2-P. By monitoring an autocatalyzed isotope exchange reaction, three stretching vibrations of the transiently bound phosphate group were selectively observed against a background of 50,000 protein vibrations. They were found at 1194, 1137, and 1115 cm–1. This information was evaluated using the bond valence model and empirical correlations. Compared with the model compound acetyl phosphate, structure and charge distribution of the E2-P aspartyl phosphate resemble somewhat the transition state in a dissociative phosphate transfer reaction; the aspartyl phosphate of E2-P has 0.02 Å shorter terminal P–O bonds and a 0.09 Å longer bridging P–O bond that is ∼20% weaker, the angle between the terminal P–O bonds is wider, and –0.2 formal charges are shifted from the phosphate group to the aspartyl moiety. The weaker bridging P–O bond of E2-P accounts for a 1011–1015-fold hydrolysis rate enhancement, implying that P–O bond destabilization facilitates phosphoenzyme hydrolysis. P–O bond destabilization is caused by a shift of noncovalent interactions from the phosphate oxygens to the aspartyl oxygens. We suggest that the relative positioning of Mg2+ and Lys684 between phosphate and aspartyl oxygens controls the hydrolysis rate of the ATPase phosphoenzymes and related phosphoproteins.
Alzheimer’s disease (AD) is the most common neurodegenerative disorder world wide, causing presenile dementia and death of millions of people. During AD damage and massive loss of brain cells occur. Alzheimer’s disease is genetically heterogeneous and may therefore represent a common phenotype that results from various genetic and environmental influences and risk factors. In approximately 10% of patients, changes of the genetic information were detected (gene mutations). In these cases, Alzheimer’s disease is inherited as an autosomal dominant trait (familial Alzheimer’s disease, FAD). In rare cases of familial Alzheimer’s disease (about 1-3%), mutations have been detected in genes on chromosomes 14 and 1 (encoding for Presenilin 1 and 2, respectively), and on chromosome 21 encoding for the amyloid precursor protein (APP), which is responsible for the release of the cell-damaging protein amyloid-beta (ß-amyloid, Aß). Familial forms of early-onset Alzheimer’s disease are rare; however, their importance extends far beyond their frequency, because they allow to identify some of the critical pathogenetic pathways of the disease. All familial Alzheimer mutations share a common feature: they lead to an enhanced production of the Aß, which is the major constituent of senile plaques in brains of AD patients. New data indicates that Aß promotes neuronal degeneration. Therefore, one aim of these thesis was to elucidate the neurotoxic biochemical pathways induced by Aß, investigating the effect of the FAD Swedish APP double mutation (APPsw) on oxidative stress-induced cell death mechanisms. This mutation results in a three- to sixfold increased Aß production compared to wild-type APP (APPwt). As cell models, the neuronal PC12 (rat pheochromocytoma) and the HEK (human embryonic kidney 293) cell lines were used, which have been transfected with human wiltyp APP or human APP containing the Swedish double mutation. The used cell models offer two important advantages. First, compared to experiments using high concentrations of Aß at micromolar levels applied extracellularly to cells, PC12 APPsw cells secret low Aß levels similar to the situation in FAD brains. Thus, this cell model represents a very suitable approach to elucidate the AD-specific cell death pathways mimicking physiological conditions. Second, these two cell lines (PC12 and HEK APPwt and APPsw) with different production levels of Aß may additionally allow to study dose-dependent effects of Aß. The here obtained results provide evidence for the enhanced cell vulnerability caused by the Swedish APP mutation and elucidate the cell death mechanism probably initiated by intracellulary produced Aß. Here it seems likely that increased production of Aß at physiological levels primes APPsw PC12 cells to undergo cell death only after additional stress, while chronic high levels in HEK cells already lead to enhanced basal apoptotic levels. Crucial effects of the Swedish APP mutation include the impairments of cellular energy metabolism affecting mitochondrial membrane potential and ATP levels as well as the additional activation of caspase 2, caspase 8 and JNK in response to oxidative stress. Thereby ,the following model can be proposed: PC12 cells harboring the Swedish APP mutation have a reduced energy metabolism compared to APPwt or control cells. However, this effect does not leads to enhanced basal apoptotic levels of cultured cells. An exposure of PC12 cells to oxidative stress leads to mitochondrial dysfunction, e.g., decrease in mitochondrial membrane potential and depletion in ATP. The consequence is the activation of the intrinsic apoptotic pathway releasing cytochrome c and Smac resulting in the activation of caspase 9. This effect is amplified by the overexpression of APP, since both APPsw and APPwt PC12 cells show enhanced cytochrome c and Smac release as well as enhanced caspase 9 activity as vector transfected control. In APPsw PC12 cells a parallel pathway is additionally emphased. Due to reduced ATP levels or enhanced Aß production JNK is activated. Furthermore, the extrinsic apoptotic pathway is enhanced, since caspase 8 and caspase 2 activation was clearly enhanced by the Swedish APP mutation. Both pathways may then converge by activating the effector enzyme, caspase 3, and the execution of cell death. In addition, caspase independent effects also needs to be considered. One possibility could be the implication of AIF since AIF expression was found to be induced by the Swedish APP mutation. In APPsw HEK cells high chronic Aß levels leads to enhanced apoptotic levels, reduce mitochondrial membrane potential and ATP levels even under basal conditions. Summarizing, a hypothetical sequence of events is proposed linking FAD, Aß production, JNK-activation, mitochondrial dysfunction with caspase pathway and neuronal loss for our cell model. The brain has a high metabolic rate and is exposured to gradually rising levels of oxidative stress during life. In Swedish FAD patients the levels of oxidative stress are increased in the temporal inferior cortex. This study using a cell model mimicking the in vivo situation in AD brains indicates that probably both, increased Aß production and the gradual rise of oxidative stress throughout life converge at a final common pathway of an increased vulnerability of neurons to apoptotic cell death from FAD patients. Presenilin (PS) 1 is an aspartyl protease, involved in the gamma-secretase mediated proteolysis of Amyloid-ß-protein (Aß), the major constituent of senile plaques in brains of Alzheimer’s disease (AD) patients. Recent studies have suggested an additional role for presenilin proteins in apoptotic cell death observed in AD. Since PS 1 is proteolytic cleaved by caspase 3, it has been prosposed that the resulting C-terminal fragment of PS1 (PSCas) could play a role in signal transduction during apoptosis. Moreover, it was shown that mutant presenilins causing early-onset of familial Alzheimer's disease (FAD) may render cells vulnerable to apoptosis. The mechanism by which PS1 regulates apoptotic cell death is yet not understood. Therefore one aim of our present study was to clarify the involvement of PS1 in the proteolytic cascade of apoptosis and if the cleavage of PS1 by caspase 3 has an regulatory function. Here it is demonstrated that both, PS1 and PS1Cas lead to a reduced vulnerability of PC12 and Jurkat cells to different apoptotic stimuli. However a mutation at the caspase 3 recognition site (D345A/ PSmut), which inhibits cleavage of PS1 by caspase 3, show no differences in the effect of PS1 or PSCas towards apoptotic stimuli. This suggest that proteolysis of PS1 by caspase 3 is not a determinant, but only a secondary effect during apoptosis. Since several FAD mutation distributed through the whole PS1 gene lead to enhanced apoptosis, an abolishment of the antiapoptotic effect of PS1 might contribute to the massive neurodegeneration in early age of FAD patients. Here, the regulate properties of PS1 in apoptosis may not be through an caspase 3 dependent cleavage and generation of PSCas, but rather through interaction of PS1 with other proteins involved in apoptosis.