The 'Open Method of Coordination' as an Instrument for Implementing the Principle of Subsidiarity? WP C.S.D.L.E. "Massimo D'Antona" N. 33/2005

[From the Introduction]. Since the Treaty of Maastricht (1992), later incorporated in the Treaty of Amsterdam (1997), the concept of ‘subsidiarity’ has become a prominent part of the constitutional order of the European Union. Since 1992, the Commission publishes a report each year on the application of the principle of subsidiarity. Also, in the recent debates about the Constitutional Treaty, reference has often been made to this principle for or against certain proposals how the relations between the Union and the Member States should be regulated. Indeed, in a multi-level political system like the European Union, it is an issue of crucial importance how competences are divided and shared between the different levels of government (European, national, regional, communal). At least for someone who comes from a federal state like the Federal Republic of Germany, it is somewhat surprising that the notion of ‘federalism’ is not mentioned in this context, and is almost banned from the official vocabulary of the EU. For the very same problems of an adequate division of responsibilities and powers between the different levels of government pose themselves in every federal political system (Scharpf 1985). It is also somewhat surprising that the notion of ‘subsidiarity’ has been adopted instead, because this concept – as it was first used in the Papal Encyclical “Quadragesimo anno” of Pope Pius XI (1931) – originally referred to the relationship between the individual and the various social communities to which individuals belong (family, church, other associations). So it can be said to refer primarily to the relationships between state and non-state actors, rather than to the relationships between different territorial levels of government

Funktionelle Charakterisierung von extrazellulären Mutationen der Rezeptortyrosinkinasen KIT und FLT3 in der akuten myeloischen Leukämie

Aktivierende Mutationen in Rezeptortyrosinkinasen spielen eine wichtige Rolle in der Pathogenese solider und hämatologischer Neoplasien, wie der akuten myeloischen Leukämie (AML). Im Rahmen dieser Arbeit wurden bislang nicht-charakterisierte Mutationen der Protoonkogene c-KIT und FLT3, die in der AML auftreten, in Zellkulturmodellen auf ihr transformierendes Potential hin untersucht. In-frame-Mutationen in Exon 8 des c-KIT-Gens, die aus kleinen Deletionen mit oder ohne Insertionen im extrazellulären Bereich bestehen, treten nahezu ausschließlich in Core-binding-Faktor-Leukämien auf und verschlechtern die Prognose der betroffenen Patienten. Drei repräsentative Exon-8-Mutationen wurden stabil in IL-3-abhängigen Ba/F3-Zellen exprimiert. Sie führten zur Hyperaktiverung des Rezeptors nach Ligandenstimulation, was sich in verstärkter Proliferation und Resistenz gegenüber Apoptose äußerte. In Rezeptor-Crosslinking-Experimenten zeigte eine repräsentative Exon-8-Mutante spontane und erhöhte liganden-induzierte Dimerisierung. Die biologischen Effekte konnten anhand einer erhöhten Phosphorylierung des nachgeordneten Signalmoleküls Mitogen-aktivierte Proteinkinase (MAPK) bestätigt werden. Im Gegensatz dazu hatte der FLT3-D324N-Single-Nukleotid-Polymorphismus, der in 6.4% von De-novo-AML-, 9.0% von CML- und 4.5% von ALL-Patientenproben detektiert wurde, keinerlei Auswirkungen auf die Prognose von AML-Patienten und wurde auch bei Kontrollpersonen gefunden (1.5%). Er wies keine funktionellen Unterschiede zu Wildtyp-FLT3 hinsichtlich Rezeptorphosphorylierung, Proliferation oder Apoptoseresistenz auf. Im Gegensatz zu Exon-8-Mutationen besitzen KIT-Mutationen in der Aktivierungsschleife, die – wie hier gezeigt wurde- die Prognose von Patienten mit günstigem Karyotyp verschlechtern, Resistenz gegenüber dem PTK-Inhibitor Imatinib. Zwei dem Imatinib nicht-verwandte Inhibitoren – PKC412 und SU5614 – wurden auf die Ansprechbarkeit von KIT-D816V getestet. Nur PKC412 war in der Lage, das spontane Wachstum von KIT-D816V-transduzierten Ba/F3-Zellen und die Rezeptorautophosphorylierung in HEK 293T-Zellen zu inhibieren. PKC412 führte überdies in den Ba/F3-Zellen zu einem deutlichen G0/G1-Arrest. Die beschriebenen In-vitro-Versuche können zwar einen ersten Einblick in die Rolle der untersuchten Mutationen in der AML bieten, tiefergehende Modelle sind jedoch vonnöten, um das Verständnis der Krankheitsentstehung in diesem Kontext zu erhöhen

Inequality and the structure of countries’ external liabilities

In this paper, we present empirical evidence that higher income inequality is associated with a greater equity share in countries’ external liabilities, and we develop a theoretical model that can explain this observation: In a small open economy with traded and non-traded goods, entry barriers depress entrepreneurial activity in non-traded industries and raise income inequality. The small number of domestic non-traded goods firms leaves room for foreign firms to operate on the domestic market, and it reduces external borrowing. The model thus suggests that barriers to entrepreneurial activity raise both inequality and the equity share in foreign liabilities. Our empirical results lend some support to this conjecture

Discerning the spatio-temporal disease patterns of surgically induced OA mouse models

Osteoarthritis (OA) is the most common cause of disability in ageing societies, with no effective therapies available to date. Two preclinical models are widely used to validate novel OA interventions (MCL-MM and DMM). Our aim is to discern disease dynamics in these models to provide a clear timeline in which various pathological changes occur. OA was surgically induced in mice by destabilisation of the medial meniscus. Analysis of OA progression revealed that the intensity and duration of chondrocyte loss and cartilage lesion formation were significantly different in MCL-MM vs DMM. Firstly, apoptosis was seen prior to week two and was narrowly restricted to the weight bearing area. Four weeks post injury the magnitude of apoptosis led to a 40–60% reduction of chondrocytes in the non-calcified zone. Secondly, the progression of cell loss preceded the structural changes of the cartilage spatio-temporally. Lastly, while proteoglycan loss was similar in both models, collagen type II degradation only occurred more prominently in MCL-MM. Dynamics of chondrocyte loss and lesion formation in preclinical models has important implications for validating new therapeutic strategies. Our work could be helpful in assessing the feasibility and expected response of the DMM- and the MCL-MM models to chondrocyte mediated therapies

Extreme enrichment in atmospheric 15N15N.

Molecular nitrogen (N2) comprises three-quarters of Earth's atmosphere and significant portions of other planetary atmospheres. We report a 19 per mil (‰) excess of 15N15N in air relative to a random distribution of nitrogen isotopes, an enrichment that is 10 times larger than what isotopic equilibration in the atmosphere allows. Biological experiments show that the main sources and sinks of N2 yield much smaller proportions of 15N15N in N2. Electrical discharge experiments, however, establish 15N15N excesses of up to +23‰. We argue that 15N15N accumulates in the atmosphere because of gas-phase chemistry in the thermosphere (>100 km altitude) on time scales comparable to those of biological cycling. The atmospheric 15N15N excess therefore reflects a planetary-scale balance of biogeochemical and atmospheric nitrogen chemistry, one that may also exist on other planets

Chronic Multi-Electrode Electromyography in Snakes

Knowledge about body motion kinematics and underlying muscle contraction dynamics usually derives from electromyographic (EMG) recordings. However, acquisition of such signals in snakes is challenging because electrodes either attached to or implanted beneath the skin may unintentionally be removed by force or friction caused from undulatory motion, thus severely impeding chronic EMG recordings. Here, we present a reliable method for stable subdermal implantation of up to eight bipolar electrodes above the target muscles. The mechanical stability of the inserted electrodes and the overnight coverage of the snake body with a sleeping bag ensured the recording of reliable and robust chronic EMG activity. The utility of the technique was verified by daily acquisition of high signal-to-noise activity from all target sites over four consecutive days during stimulus-evoked postural reactions in Amazon tree boas and Western diamondback rattlesnakes. The successful demonstration of the chronic recording suggests that this technique can improve acute experiments by enabling the collection of larger data sets from single individuals

SnakeStrike: A Low-Cost Open-Source High-Speed Multi-Camera Motion Capture System

Current neuroethological experiments require sophisticated technologies to precisely quantify the behavior of animals. In many studies, solutions for video recording and subsequent tracking of animal behavior form a major bottleneck. Three-dimensional (3D) tracking systems have been available for a few years but are usually very expensive and rarely include very high-speed cameras; access to these systems for research is limited. Additionally, establishing custom-built software is often time consuming – especially for researchers without high-performance programming and computer vision expertise. Here, we present an open-source software framework that allows researchers to utilize low-cost high-speed cameras in their research for a fraction of the cost of commercial systems. This software handles the recording of synchronized high-speed video from multiple cameras, the offline 3D reconstruction of that video, and a viewer for the triangulated data, all functions previously also available as separate applications. It supports researchers with a performance-optimized suite of functions that encompass the entirety of data collection and decreases processing time for high-speed 3D position tracking on a variety of animals, including snakes. Motion capture in snakes can be particularly demanding since a strike can be as short as 50 ms, literally twice as fast as the blink of an eye. This is too fast for faithful recording by most commercial tracking systems and therefore represents a challenging test to our software for quantification of animal behavior. Therefore, we conducted a case study investigating snake strike speed to showcase the use and integration of the software in an existing experimental setup

SLCV–a supervised learning—computer vision combined strategy for automated muscle fibre detection in cross-sectional images

Muscle fibre cross-sectional area (CSA) is an important biomedical measure used to determine the structural composition of skeletal muscle, and it is relevant for tackling research questions in many different fields of research. To date, time consuming and tedious manual delineation of muscle fibres is often used to determine the CSA. Few methods are able to automatically detect muscle fibres in muscle fibre cross-sections to quantify CSA due to challenges posed by variation of brightness and noise in the staining images. In this paper, we introduce the supervised learning-computer vision combined pipeline (SLCV), a robust semi-automatic pipeline for muscle fibre detection, which combines supervised learning (SL) with computer vision (CV). SLCV is adaptable to different staining methods and is quickly and intuitively tunable by the user. We are the first to perform an error analysis with respect to cell count and area, based on which we compare SLCV to the best purely CV-based pipeline in order to identify the contribution of SL and CV steps to muscle fibre detection. Our results obtained on 27 fluorescence-stained cross-sectional images of varying staining quality suggest that combining SL and CV performs significantly better than both SL-based and CV-based methods with regards to both the cell separation- and the area reconstruction error. Furthermore, applying SLCV to our test set images yielded fibre detection results of very high quality, with average sensitivity values of 0.93 or higher on different cluster sizes and an average Dice similarity coefficient of 0.9778

Introducing a methodological approach to determine value shares in Digital Ecosystems

Motivated by the critical yet unsolved task of fair value distribution in digital ecosystems (DEs), this study presents a methodological approach that allows us to determine ecosystem components\u27 value share to the total co-created value. Our method takes a holistic perspective on DEs. It suggests that when viewing DEs as complex networks, the value share of a component to the total co-created value stems from the network size and the interaction between the network participants. We demonstrate the applicability of the proposed method in a simulation of a Smart Living service ecosystem. Our simulation shows that our method is suitable for unraveling hitherto hidden interconnectedness between value-co-creating ecosystem components. Components that offer a low structural contribution to the total value can still play a crucial role in the network and have the most significant value share to the whole network