Prototype Foamy Virus Capsid – Nucleic Acid Interactions: Mechanistic Insights & Application for Efficient RNA Transfer

Foamy viruses (FV) represent a distinct genus in the retrovirus family and separate themselves from the large group of orthoretroviruses by various distinct features in their replication cycle (reviewed in Lindemann & Rethwilm, 2011). In gene therapy retroviruses are commonly used as vectors to deliver genetic information into target cells and also FV has been successfully used for example in a canine genetic disease model (Trobridge et al., 2009). Here we investigated the interactions between the FV capsid-forming protein ‘Gag’ and nucleic acids. We found that prototype FV (PFV) Gag binds various cellular mRNAs, incorporates them into the nascent particle and thereby enables their transfer into the cytosol of target cells. There these mRNAs can serve as template for protein translation. This feature seems uniquely efficient for PFV and we developed it further into a “RNA transfer vector system” allowing efficient transgene mRNA transfer into target cells, as showed in proof-of-principle experiments in vitro and in vivo (Hamann et al., 2014a). In parallel we started investigating the specificity in viral RNA genome packaging (Hamann et al., 2014b). To date little is known how PFV selects its RNA genome over the vast excess of cellular RNAs present in the cytosol. Elevated fundamental knowledge of this mechanism could help to make the “RNA transfer vector system” even more efficient since it would allow enrichment of certain specific “designer-RNAs” in virus particles

Observing trans-Planckian ripples in the primordial power spectrum with future large scale structure probes

We revisit the issue of ripples in the primordial power spectra caused by trans-Planckian physics, and the potential for their detection by future cosmological probes. We find that for reasonably large values of the first slow-roll parameter epsilon (> 0.001), a positive detection of trans-Planckian ripples can be made even if the amplitude is as low as 10^-4. Data from the Large Synoptic Survey Telescope (LSST) and the proposed future 21 cm survey with the Fast Fourier Transform Telescope (FFTT) will be particularly useful in this regard. If the scale of inflation is close to its present upper bound, a scale of new physics as high as 0.2 M_Planck could lead to observable signatures.Comment: 20 pages, 3 figures, uses iopart.cls; v2: 21 pages, added references, to appear in JCA

OCL-based Runtime Monitoring of JVM hosted Applications

In this paper we present an approach that enables users to monitor and verify the behavior of an application running on a virtual machine at the model level. Concrete implementations of object-oriented software usually contain a lot of technical classes. Thus, the central parts of an application, e.g., the business rules, may be hidden among peripheral functionality like user-interface classes or classes managing persistency. Our approach makes use of modern virtual machines and allows the devloper to profile an application in order to achieve an abstract monitoring and verification of central application components. We represent virtual machine bytecode in form of a so-called platform-aligned model (PAM) comprising OCL invariants and pre- and postconditions. In contrast to related work, our approach uses the original source or bytecode of the monitored application as it stands and does not require any changes. We show a prototype implementation as an extension of the UML and OCL tool USE. Also, we investigate the impact of our approach to the execution time of a monitored system

Engineering failure analysis and design optimisation with HiP-HOPS

The scale and complexity of computer-based safety critical systems, like those used in the transport and manufacturing industries, pose significant challenges for failure analysis. Over the last decade, research has focused on automating this task. In one approach, predictive models of system failure are constructed from the topology of the system and local component failure models using a process of composition. An alternative approach employs model-checking of state automata to study the effects of failure and verify system safety properties. In this paper, we discuss these two approaches to failure analysis. We then focus on Hierarchically Performed Hazard Origin & Propagation Studies (HiP-HOPS) - one of the more advanced compositional approaches - and discuss its capabilities for automatic synthesis of fault trees, combinatorial Failure Modes and Effects Analyses, and reliability versus cost optimisation of systems via application of automatic model transformations. We summarise these contributions and demonstrate the application of HiP-HOPS on a simplified fuel oil system for a ship engine. In light of this example, we discuss strengths and limitations of the method in relation to other state-of-the-art techniques. In particular, because HiP-HOPS is deductive in nature, relating system failures back to their causes, it is less prone to combinatorial explosion and can more readily be iterated. For this reason, it enables exhaustive assessment of combinations of failures and design optimisation using computationally expensive meta-heuristics. (C) 2010 Elsevier Ltd. All rights reserved

How Does Restructuring Contribute to Union Revitalization?

[Excerpt] As we look cross-nationally at labour movement revitalization, we see a complex process of change that varies depending on the socio-political/economic context. Although we observe a diverse set of union strategies and outcomes, we find that structural adjustment is a common element of revitalization efforts. The mere presence of restructuring does not, of course, assure positive results. In this chapter we define various forms of restructuring, outline factors that shape and promote restructuring, and discuss the likelihood that restructuring leads to union revitalization by using examples from our cross-country comparison

Exploring (Meta-)Model Snapshots by Combining Visual and Textual Techniques

One central task in software development by means of graph-based techniques is to inspect and to query the underlying graph. Important issues are, for example, to detect general graph properties like connectivity, to explore more special features like the applicability of left-hand side rules in graph transformations, or to validate snapshots of evolving systems by checking properties in an on-the-fly way. We propose a new approach combining visual and textual techniques for exploring graphs. We emphasize a particular aspect of the underlying graph by showing or hiding nodes and edges. We offer three different ways to explore (meta-)model snapshots which may be combined: (1) selection by object identity and class membership, (2) selection by OCL expression, and (3) selection by path length. One main motivation for our work is to access large or complicated graphs in a systematic way. We evaluate our approach by different middle-sized scenarios. Our evaluation shows that the approach works for large graphs with about 1000 nodes and 2000 edges and for graphs which instantiate metamodels representing software engineering artifacts

Optimierte Suche von Modellinstanzen UML/OCL-Beschreibungen in USE

National audienceKonzeptuelle Modelle sind ein wichtiges Element modellgetriebener Softwareentwicklung, sowohl in der Beschreibung von Systemen als auch in der Metamodellierung domänenspezifischer Sprachen. Zu ihrer Beschreibung haben sich UML und OCL (und angelehnte Sprachen) als ein de facto Standard durchgesetzt. Validierung und Verifikation der Modelle sind hierbei wichtige Instrumente zur Sicherstellung der Modellqualität. Die Sprache ASSL (A Snapshot Sequence Language) bietet die Möglichkeit durch imperative Programmierung auf Modellebene und Backtracking konforme Instanzen systematisch zu erzeugen. Der White-Box-Ansatz ASSL ergänzt Black-Box-Ansätze, welche die Modellinstanziierung durch Abbildung auf (bspw.) ein Problem der relationalen Logik lösen. Dieser Beitrag beschreibt, wie die durch ASSL-Programme aufgespannten Suchräume durch Ausnutzung der Modellabdeckung der OCL-Constraints und der Modellstruktur erheblich verkleinert werden können und gibt einen Ausblick darauf, wie bestehende Black-Box-Ansätze in ASSL integriert werden können, um innerhalb eines imperativen Rahmens Teilinstanziierungen deklarativ beschreiben zu können

Abstract runtime monitoring with USE

Adsorption and photodecomposition of formic acid on rutile TiO2 (110) have been investigated with infrared reflection–absorption spectroscopy (IRRAS) employing p- and s-polarized light along the [001] and [ 11⎯⎯0 ] crystal directions. The single crystal surfaces were prepared either by sputtering and annealing in ultrahigh vacuum (UHV) to obtain a reduced surface (r-TiO2), or by sputtering without annealing to create a rough, highly defective surface (sp-TiO2). Results are compared with corresponding measurements on rutile nanocrystals performed in synthetic air. IRRAS spectra obtained on r-TiO2 and rutile nanocrystals are very similar, and show that in both cases formic acid dissociates and is predominately adsorbed as a bridging bidentate formate species, and that the formate adsorption structure on the nanocrystals is dominated by interactions with majority (110) surfaces. In contrast, the IRRAS spectra on sp-TiO2 are different, with only minor spectral features associated with (110) surfaces and lost azimuthal symmetry, both of which imply changed adsorption geometry due to bonding to low-coordinated Ti atoms with lower valences. The UV-induced rate of formate photodecomposition is about 30 times higher on rutile nanocrystals in synthetic air compared with sp-TiO2 under UHV conditions, and even larger than on r-TiO2. These differences are explained by the lack of oxygen and limited hydroxyl coverage under UHV conditions. The difference in reactivity between the r-TiO2 and sp-TiO2 surfaces is attributed to a high concentration of strongly bonded bridging bidentate formate species on the (110) surface, which lowers its reactivity. The results point to a pressure gap where the availability of molecular oxygen and the hydroxyl concentration limit the photoreactivity in UHV leading to an almost 20-fold decrease of the formate degradation rate in UHV. In contrast, the structure represented by the single crystal (110) surface is shown to capture the essential structural properties, which dictates the formic acid adsorption and adsorption structure of rutile nanocrystals