Identifizierung und Validierung funktioneller Intrabodies zur Inhibition von Protein-Protein-Wechselwirkungen bei SCA2.

Dysfunktionale Protein-Protein-Interaktionen können für die Ausbildung von Krebs oder Neurodegenerativen Erkrankungen von entscheidender Bedeutung sein. Um die Ursache dieser Krankheiten zu verstehen benötigt man Liganden, die in Proteininteraktionsnetzwerke eingreifen. Ziel dieser Arbeit ist es einen 2-Stufen in vivo/in vitro Assay zur Selektion von Intrabodies (Antikörperfragmente, die im Innern der Zelle wirksam sind) zu etablieren, die Protein-Protein-Interaktionen inhibieren und dabei Schwierigkeiten und Besonderheiten derartiger Screens, wie die potenziell oligoklonale Hefe oder Falschpositive zu begegnen und einer Lösung zuzuführen. Mittels standardisierten, optimierten Bedingungen soll eine Intrabody-Screen-Methode gegen beliebige Targets etabliert werden. Man hätte so ein Werkzeug um einzelne Funktionen eines Proteins wie bestimmte Interaktionen oder enzymatische Funktionen gezielt zu beeinflussen, ohne das gesamte Protein auszuknocken. Dies würde neue Möglichkeiten zur Untersuchung von (Fehl-)Funktionen von Proteinen ermöglichen. Des Weiteren wäre es denkbar Intrabodies, aufgrund ihrer Analogie zu Antikörpern, als Therapeutikum zur Behandlung bisher unheilbarer Krankheiten beim Menschen zu verwenden

The Effect of Randomness on the Mott State

We reinvestigate the competition between the Mott and the Anderson insulator state in a one-dimensional disordered fermionic system by a combination of instanton and renormalization group methods. Tracing back both the compressibility and the ac-conductivity to a vanishing kink energy of the electronic displacement field we do not find any indication for the existence of an intermediate (Mott glass) phase.Comment: 4 page

Grammaticality judgments and linguistic methodology

Throughout much of the history of linguistics, grammaticality judgments – intuitions about the well-formedness of sentences – have constituted most of the empirical base against which theoretical hypothesis have been tested. Although such judgments often rest on subtle intuitions, there is no systematic methodology for eliciting them, and their apparent instability and unreliability have led many to conclude that they should be abandoned as a source of data. Carson T. Schütze presents here a detailed critical overview of the vast literature on the nature and utility of grammaticality judgments and other linguistic intuitions, and the ways they have been used in linguistic research. He shows how variation in the judgment process can arise from factors such as biological, cognitive, and social differences among subjects, the particular elicitation method used, and extraneous features of the materials being judged. He then assesses the status of judgments as reliable indicators of a speaker's grammar. Integrating substantive and methodological findings, Schütze proposes a model in which grammaticality judgments result from interaction of linguistic competence with general cognitive processes. He argues that this model provides the underpinning for empirical arguments to show that once extragrammatical variance is factored out, universal grammar succumbs to a simpler, more elegant analysis than judgment data initially lead us to expect. Finally, Schütze offers numerous practical suggestions on how to collect better and more useful data. The result is a work of vital importance that will be required reading for linguists, cognitive psychologists, and philosophers of language alike. "Native speakers' judgments of the acceptability of linguistic examples have always formed a major part of the data of linguistics, but linguists generally either have elicited such data in a haphazard fashion and accepted the results uncritically or have rejected acceptability judgments altogether and equally uncritically. Schütze's book is a welcome relief from the failure of linguists to deal responsibly with what can be either the most fertile or the most misleading source of information about languages." —James D. McCawley, University of Chicago "Schütze has written an extraordinarily useful and timely book. In it, he provides a clear and readable review of past studies of the methodology of generative syntax. But this is not merely a survey: it is also a call for more careful and objective scientific methods in syntax, including a set of practical methodological suggestions for working syntacticians. If heeded, they will greatly strengthen the empirical base of linguistic theory." —Tom Wasow, Stanford Universit

INFL in child and adult language : agreement, case and licensing

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Linguistics and Philosophy, 1997.Includes bibliographical references (p. 280-292).by Carson Theodore Robert Schütze.Ph.D

Influence of measurement uncertainty on machine learning results demonstrated for a smart gas sensor

Humans spend most of their lives indoors, so indoor air quality (IAQ) plays a key role in human health. Thus, human health is seriously threatened by indoor air pollution, which leads to 3.8 ×106 deaths annually, according to the World Health Organization (WHO). With the ongoing improvement in life quality, IAQ monitoring has become an important concern for researchers. However, in machine learning (ML), measurement uncertainty, which is critical in hazardous gas detection, is usually only estimated using cross-validation and is not directly addressed, and this will be the main focus of this paper. Gas concentration can be determined by using gas sensors in temperature-cycled operation (TCO) and ML on the measured logarithmic resistance of the sensor. This contribution focuses on formaldehyde as one of the most relevant carcinogenic gases indoors and on the sum of volatile organic compounds (VOCs), i.e., acetone, ethanol, formaldehyde, and toluene, measured in the data set as an indicator for IAQ. As gas concentrations are continuous quantities, regression must be used. Thus, a previously published uncertainty-aware automated ML toolbox (UA-AMLT) for classification is extended for regression by introducing an uncertainty-aware partial least squares regression (PLSR) algorithm. The uncertainty propagation of the UA-AMLT is based on the principles described in the Guide to the Expression of Uncertainty in Measurement (GUM) and its supplements. Two different use cases are considered for investigating the influence on ML results in this contribution, namely model training with raw data and with data that are manipulated by adding artificially generated white Gaussian or uniform noise to simulate increased data uncertainty, respectively. One of the benefits of this approach is to obtain a better understanding of where the overall system should be improved. This can be achieved by either improving the trained ML model or using a sensor with higher precision. Finally, an increase in robustness against random noise by training a model with noisy data is demonstrated.</p

Accelerated reliability testing of articulated cable bend restrictor for offshore wind applications

PublishedFinal report.Power cable failures for offshore marine energy applications are a growing concern since experience from offshore wind has shown repeated failures of inter-array and export cables. These failures may be mitigated by dedicated cable protection systems, such as bend restrictors. This study presents the rationale and the results for accelerated reliability tests of an articulated bend restrictor. The tests are a collaborative effort between the University of Exeter, CPNL Engineering and NSW, supported by the EU Marinet Programme. The tests have been carried out at full - scale and exposed the static submarine power cable – bend restrictor specimen to mechanical load regimes exceeding the allowable design loads in order to provoke accelerated wear and component failures. The tested load cases combined cyclic bending motions with oscillating tensile forces. A range of acceleration factors have been applied in respect to the 1:50 years load case, subjecting each of the three restrictor samples to 25,000 bending cycles (50,000 tensile cycles). The static power cable was also loaded beyond its intended use, testing the worst case scenario of repeated dynamic loading, purposely inflicting failure modes for investigation. Throughout the test the static submarine power cable sustained over 77,000 bending cycles (154,000 tensile cycles). The test demonstrated the integrity of the cable protection system with quantified wear rates obtained through 3D scanning of the individual shells. The static power cable also showed a high reliability level. None of the failure modes, mainly fatigue cracks and fretting, identified by cable dissection would have caused direct loss of service. The observed failure modes could also be predicted through numerical load analysis, giving confidence in the utilised mechanical modelling and cross - sectional analysis for dynamic applications. Overall the study shows how dedicated collaborative component testing can make an important contribution to quantify and validate component behaviour in challenging offshore operating environments.The work described in this publication has received support from MARINET, a European Community - Research Infrastructure Action under the FP7 “Capacities” Specific Programme

Objectless locative prepositions in British English

In British English, sentences like This film has monsters in are possible without the pronoun it. Descriptively, we refine landscape of the phenomenon, identifying restrictions on the distribution and interpretation of OLPs, including dialectal variation within British English, and observing an A-bar movement restriction on monsters. Analytically, we argue against an A-movement analysis (Griffiths & Sailor), and ponder alternatives from a cross-linguistic perspective

Transparent free relatives with "who": Support for a unified analysis

This paper provides novel data, including from acceptability ratings, supporting a unified analysis of Transparent Free Relatives (TFRs) as variants of Standard Free Relatives (SFRs), rather than entirely different beasts. Two arguments are presented. First, who-TFRs exist, contrary to the view in the literature that TFRs can only be formed with what. Second, who-TFRs degrade following the same illunderstood pattern as who-SFRs. These outcomes cohere better with accounts of TFRs that treat them as similar to SFRs, versus accounts that treat them as virtually unrelated

Kinetic modelling of methanol synthesis over commercial catalysts: A critical assessment

Kinetic modelling of methanol synthesis over commercial catalysts is of high importance for reactor and process design. Literature kinetic models were implemented and systematically discussed against a newly developed kinetic model based on published kinetic data. Deviations in the sensitivities of the kinetic models were explained by means of the experimentally covered parameter range. The simulation results proved that an extrapolation of the working range of the kinetic models can lead towards significant simulation errors especially with regard to pressure, stoichiometric number and CO/CO$_{2}$-ratio considerably limiting the applicability of kinetic models frequently applied in scientific literature. Therefore, the validated data range for kinetic models should be considered when detailed reactor simulations are carried out. With regard to Power-to-Methanol processes special attention should be drawn towards the rate limiting effect of water at high CO$_{2}$ contents in the syngas. Moreover, it was shown that kinetic models based on data measured over outdated catalysts show significantly lower activity than those derived from state-of-the-art catalysts and should therefore be applied with caution for reactor and process simulations. The plausible behavior of the herein proposed kinetic model was demonstrated by a systematic comparison towards established kinetic approaches within both, an ideal kinetic reactor and an industrial steam cooled tubular reactor. Relative to the state-of-the-art kinetic models it was proven that the herein proposed kinetic model can be applied over the complete industrially relevant working range for methanol synthesis