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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.