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Requirements Engineering (RE) plays a critical role in software system development and is argued to be the key leverage point for practitioners who want to design sustainable software-intensive systems. However, existing RE methods and tools do not explicitly facilitate the discussion and negotiation of sustainability-related concerns. This leads to insufficient or onedimensional perceptions of sustainability. In this paper, we discuss our understanding of sustainability and its relationship with requirements. Based on the outcomes of this discussion, we have extended the WinWin Negotiation Model by incorporating sustainability concepts so that the negotiation also includes the ability to consider the impact of requirements on sustainability. Applying this negotiation method in an exploratory industrial case study, we have learned that this approach stimulates the discussion on sustainability and its multiple dimensions. It also allows practitioners to reflect on requirements and their effects on sustainability. However, we have also observed that further in-depth requirements analysis is needed to analyse the long-term effects of requirements regarding sustainability.

Quantum gases in optical lattices offer a well-controlled and defect free environment to simulate and study phenomena from condensed matter physics. In particular, questions related to conductivity and charge carrier mobility lie at the heart of the properties of many fascinating materials like superconductors, graphene and semiconductors. The latter become conductive if irradiated with photons. This effect is called photoconductivity and results from photon-induced interband transitions of electrons, leading to the creation of electron and hole excitations, which subsequently serve as free charge carriers. Photoconductivity is widely used in technological applications such as semiconductor photodiodes and photoresistors and as a powerful probe for novel materials.

In this paper the authors present the first experiments loading a Bose-Einstein condensate into a triangular optical lattice. The lattice is formed by three interfering laser beams intersecting at a relative angle of 120deg in one plane in addition to one retroreflected beam perpendicular to this plane. Depending on the strength of this last beam, the lattice potential can be tuned from a triangular lattice of Id tubes to a Id stack of 2d triangular lattice sheets. As an interesting aspect, the triangular lattice can be transformed into a "magnetic" hexagonal one with sublattices for the different spin orientations, just by rotating the laser polarization.

During the last decade the physics of ultracold quantum gases has matured into a highly active and versatile field of research. Experiments dedicated to the physics of Bose-Einstein condensates have been performed and diverse phenomena, which are distinguished by fundamentally different regimes of interaction, can be investigated. Particularly solitons, characterized as non-spreading wavepackets, are stabilized against dispersion by a suitable non-linear interaction and can propagate in a condensate[1,2]. In the present work the dynamical evolution of long-lived dark solitons has been studied as a paradigm of non-linear physics for the first time. We have been able to observe oscillations of dark solitons in elongated Bose-Einstein condensates and good agreement with the theoretically predicted oscillation frequency of ω/√2 has been obtained [1]. Moreover the results of detailed studies of the collision of two dark solitons distinguished by different depths are presented. This particular feature enables the identification of the individual solitons beyond the actual collision process and as a central result we show shown that these peculiar entities interpenetrate without significantly influencing each other [3]. The theoretical description of solitons as weakly interacting quasi particles is in good agreement with these findings. Continuative studies on vectorial “dark-bright” solitons and their dynamical properties complement the investigations on dark solitons.

SUMMARYImmunosuppressive therapy with methotrexate (MTX) has been established as effective treatment for patients with rheumatoid arthritis. To analyse the therapeutic potential and mechanisms of action of MTX, we determined serum cytokine levels and cytokine production by splenic T cells and macrophages in untreated and MTX-treated mice. Furthermore, we assessed the role of MTX in a murine model of experimental arthritis induced by collagen type II (CIA). MTX reduced spontaneous and IL-15-induced tumour necrosis factor (TNF) production by splenic T cells but not by macrophages from healthy mice in vitro in a dose-dependent manner. In contrast, interferon-gamma (IFN-γ) production was less strikingly reduced and IL-4 production was virtually unaffected. In addition, treatment of healthy mice with MTX in vivo led to reduced TNF serum levels and diminished TNF production by splenic T cells and macrophages. Intraperitoneal administration of MTX prior to the onset of arthritis completely prevented clinical and pathological signs of CIA. This was associated with a striking reduction of TNF production by spleen cells from MTX-treated mice. The role of TNF in MTX-mediated effects on cytokine production was further underlined by the finding that MTX effects on IFN-γ production were augmented in TNF-transgenic mice but abrogated in mice in which the TNF-α gene had been inactivated by homologous recombination. Thus, MTX specifically modulates spontaneous and IL-15-induced TNF-α production in mice and prevents experimental murine CIA. These data suggest that TNF production by T cells is an important target of MTX and may serve as a basis to understand and further analyse MTX-mediated mechanisms of immunosuppression in patients with RA.

Tumor progression locus-2 (Tpl2) kinase is a major inflammatory mediator in immune cell types recently found to be genetically associated with inflammatory bowel diseases (IBDs). Here we show that Tpl2 may exert a dominant homeostatic rather than inflammatory function in the intestine mediated specifically by subepithelial intestinal myofibroblasts (IMFs). Mice with complete or IMF-specific Tpl2 ablation are highly susceptible to epithelial injury-induced colitis showing impaired compensatory proliferation in crypts and extensive ulcerations without significant changes in inflammatory responses. Following epithelial injury, IMFs sense innate or inflammatory signals and activate, via Tpl2, the cyclooxygenase-2 (Cox-2)- prostaglandin E2 (PGE2) pathway, which we show here to be essential for the epithelial homeostatic response. Exogenous PGE2 administration rescues mice with complete or IMF-specific Tpl2 ablation from defects in crypt function and susceptibility to colitis. We also show that Tpl2 expression is decreased in IMFs isolated from the inflamed ileum of IBD patients indicating that Tpl2 function in IMFs may be highly relevant to human disease. The IMF-mediated mechanism we propose also involves the IBD-associated genes IL1R1, MAPK1, and the PGE2 receptor-encoding PTGER4. Our results establish a previously unidentified myofibroblast-specific innate pathway that regulates intestinal homeostasis and may underlie IBD susceptibility in humans.

Summary Our aim in this study was to search for lung parenchyma alterations associated with asbestos and/or asbestos-like fiber concentration. This was done by means of immuno- or glycohistochernistry. The hot-ashing technique determined the asbestos and asbestos-like fiber concentrations in the lung tissues of 100 patients of whom 52 were treated for primary lung and 25 for secondary lung tumors; fiber concentration was also measured for 23 patients whose disease was benign. The results were correlated to smoking habits, survival of the patients, and expression of binding capacities for endogenous lectins, natural carbohydrate-binding and lectin-specific antibodies. The cohort with proven asbestos exposure revealed a mean fiber concentration 114 f/g compared to 95 f/g in the non-exposed group. An increased asbestos fiber concentration was correlated to galectin-1-binding and the presence of epitopes for natural immunoglobulin G subfractions with selectivity to α-galactosides and α-mannosides. The survival of patients with primary and secondary lung tumors was negatively associated with the fiber concentration. The data indicate that increased presence of asbestos is correlated with an alteration of defined glycohistochemical features of alveolar lining cells.

Sustainability has emerged as a broad concern for society. Many engineering disciplines have been grappling with challenges in how we sustain technical, social and ecological systems. In the software engineering community, for example, maintainability has been a concern for a long time. But too often, these issues are treated in isolation from one another. Misperceptions among practitioners and research communities persist, rooted in a lack of coherent understanding of sustainability, and how it relates to software systems research and practice. This article presents a cross-disciplinary initiative to create a common ground and a point of reference for the global community of research and practice in software and sustainability, to be used for effectively communicating key issues, goals, values and principles of sustainability design for software-intensive systems. The centrepiece of this effort is the Karlskrona Manifesto for Sustainability Design, a vehicle for a much needed conversation about sustainability within and beyond the software community, and an articulation of the fundamental principles underpinning design choices that affect sustainability. We describe the motivation for developing this manifesto, including some considerations of the genre of the manifesto as well as the dynamics of its creation. We illustrate the collaborative reflective writing process and present the current edition of the manifesto itself. We assess immediate implications and applications of the articulated principles, compare these to current practice, and suggest future steps.

A breakthrough in cold atom quantum technology is hindered by a bottleneck in the supporting technologies. We discuss a cold atom technology platform developed within the European iSense project, aiming at a gravimeter as demonstrator.

We have shown recently that the azathioprine metabolite 6-Thio-GTP causes immunosuppression by blockade of GTPase activation in T lymphocytes. In the present study, we describe a new molecular mechanism by which 6-Thio-GTP blocks GTPase activation. Although 6-Thio-GTP could bind to various small GTPases, it specifically blocked activation of Rac1 and Rac2 but not of closely related Rho family members such as Cdc42 and RhoA in primary T cells upon stimulation with αCD28 or fibronectin. Binding of 6-Thio-GTP to Rac1 did not suppress Rac effector coupling directly but blocked Vav1 exchange activity upon 6-Thio-GTP hydrolysis, suggesting that 6-Thio-GTP loading leads to accumulation of 6-Thio-GDP-loaded, inactive Rac proteins over time by inhibiting Vav activity. In the absence of apoptosis, blockade of Vav-mediated Rac1 activation led to a blockade of ezrin-radixin-moesin dephosphorylation in primary T cells and suppression of T cell-APC conjugation. Azathioprine-generated 6-Thio-GTP thus prevents the development of an effective immune response via blockade of Vav activity on Rac proteins. These findings provide novel insights into the immunosuppressive effects of azathioprine and suggest that antagonists of the Vav-Rac signaling pathway may be useful for suppression of T cell-dependent pathogenic immune responses.

To methodically evaluate the reproducibility and accuracy of coronary arterial calcification measurements by using spiral multi-detector row and electron-beam computed tomography (CT) with a beating heart phantom.A phantom was built to mimic a beating heart with coronary arteries and calcified plaques. The simulated vessels moved in a pattern similar to that of a beating heart. The phantom operated at a variety of pulse rates (0-140 beats per minute). The phantom was repeatedly scanned in various positions by using various protocols with electron-beam and multi-detector row CT scanners to assess interexamination variability. Statistical analysis was performed to determine significant differences in interexamination variability for various acquisition protocols.Electrocardiographically (EKG) gated volume coverage with spiral multi-detector row CT (2.5-mm collimation) and overlapping image reconstruction (1-mm increment) was found to significantly improve the reliability of coronary arterial calcium quantification, especially for small plaques (P.05). Mean interexamination variability was reduced from 35% +/- 6 (SD) (Agatston score, standard electron-beam CT) to 4% +/- 2 (P.05) (volumetric score, spiral EKG-gated multi-detector row CT).By coupling retrospective gating with nearly isotropic volumetric imaging data, spiral multi-detector row CT provides better input data for quantification of coronary arterial calcium volume. Multi-detector row CT allows precise and repeated measurement of coronary arterial calcification, with low interexamination variability.

By proteolysis, the enzymatic cleavage of peptide bonds, proteins undergo an irreversible posttranslational modification which is used for protein maturation, signaling and cellular adhesion. The work of this thesis approaches the role of the extracellular metalloproteases meprin α and meprin β in physiological and pathological conditions, especially in skin and inflammation related diseases. The first part of this thesis addresses the meprin expression in murine skin and their resulting role in wound healing and deposition of extracellular matrix in this organ. Based on previous findings that meprins are over-expressed in fibrotic and hyperkeratotic skin diseases, we analyzed mouse models over-expressing meprin β in skin in order to study its contribution to the onset of disease. Fra2 transgenic mice develop skin fibrosis and over-express meprin β in skin. Since Fra2 activates several other genes besides the meprin β gene, mouse models directly over-expressing meprin β in skin were generated. Epidermal over-expression of meprin β led to a pigmentary phenotype and hyperproliferation of keratinocytes. On the other hand, a dermal over-expression of meprin β did not show an obvious phenotype or development of fibrosis. The second part focused on proteolytic processing of the adhesion molecule CD99. Cleavage of CD99 by meprin β had an effect on transendothelial migration of cancer cells and inhibition of meprin β delayed infiltration of immune cells in an acute inflammation model. Finally, altered localization of meprin α was investigated during pathological conditions. Under normal conditions, soluble meprin α was observed to bind to epithelial cells via heparan sulphate, which had impact on infiltration of immune cells and epithelial barrier integrity. Moreover, covalent binding of meprin α to meprin β on the secretory pathway could also tether soluble meprin α to the plasma membrane. The altered localization of meprin α contributed to inflammatory disease progression.

Meprin α und Meprin β sind Zink abhängige Metalloendoproteasen, die zur Astacin Peptidasenfamilie zählen. Meprine sind in humanen Pathologien wie Fibrose und der Generierung von Amyloid β Peptiden relevant. Um Meprine in Erkrankungen als therapeutische Moleküle einzusetzen, ist das Verständnis der Regulation ihrer proteolytischen Aktivität bedeutsam. Erstmals wurde in dieser Arbeit nachgewiesen, dass membrangebundenes Promeprin β nicht durch lösliche Proteasen aktiviert werden kann. Trypsin, der potenteste bekannte Meprin Aktivator, konnte membrangebundenes Promeprin β nicht maturieren. Somit bestätigte sich die initial aus der Meprin β Kristallstruktur entwickelte Hypothese, dass lösliche Aktivatoren keinen Zugang zur nahe der Zellmembran gelegenen Propeptid Spaltstelle erhalten und eine membrangebundene Protease zur Aktivierung notwendig ist. Es wurde Matriptase 2 als erster membrangebundener Aktivator von Promeprin β identifiziert. Dies wurde in Meprin β und Matriptase 2 Ko-Transfektionsansätzen mittels Immunoblots sowie Bestimmung der spezifischen proteolytischen Meprin β Aktivität an der Zelloberfläche validiert. Massenspektrometrische Untersuchungen identifizierten die Spaltstelle im Meprin β Propeptid an Position Arg 61/ Asn 62. In Überexpressionsstudien wurde die Kolokalisation von Meprin β und Matriptase 2 auf der Membran detektiert. Promeprin α wird nicht durch Matriptase 2 aktiviert. Zudem konnte von humanen Fibroblasten exprimiertes Prokollagen I als Meprin Substrat validiert werden. Deshalb wurde die proteolytische Meprin Aktivität mit selektierten Inhibitoren in humanen dermalen Fibroblasten reguliert. Dies resultierte in einer reduzierten Prokollagen I Maturierung im Zelllysat. Die Ergebnisse eröffnen interessante Perspektiven für zukünftige Forschungsprojekte. Es könnte die Beteiligung der Matriptase 2 bei Meprin β induzierten Pathologien und die Applikation selektiver Meprin Inhibitoren in geeigneten in vivo Fibrose Modellen analysiert werden.