Adenosine Kinase of T. b. Rhodesiense identified as the putative target of 4-[5-(4-phenoxyphenyl)-2H-pyrazol-3-yl]morpholine using chemical proteomics

BACKGROUND: Human African trypanosomiasis (HAT), a major parasitic disease spread in Africa, urgently needs novel targets and new efficacious chemotherapeutic agents. Recently, we discovered that 4-[5-(4-phenoxyphenyl)-2H-pyrazol-3-yl]morpholine (compound 1) exhibits specific antitrypanosomal activity with an IC(50) of 1.0 microM on Trypanosoma brucei rhodesiense (T. b. rhodesiense), the causative agent of the acute form of HAT. METHODOLOGY/PRINCIPAL FINDINGS: In this work we show adenosine kinase of T. b. rhodesiense (TbrAK), a key enzyme of the parasite purine salvage pathway which is vital for parasite survival, to be the putative intracellular target of compound 1 using a chemical proteomics approach. This finding was confirmed by RNA interference experiments showing that down-regulation of adenosine kinase counteracts compound 1 activity. Further chemical validation demonstrated that compound 1 interacts specifically and tightly with TbrAK with nanomolar affinity, and in vitro activity measurements showed that compound 1 is an enhancer of TbrAK activity. The subsequent kinetic analysis provided strong evidence that the observed hyperactivation of TbrAK is due to the abolishment of the intrinsic substrate-inhibition. CONCLUSIONS/SIGNIFICANCE: The results suggest that TbrAK is the putative target of this compound, and that hyperactivation of TbrAK may represent a novel therapeutic strategy for the development of trypanocides.

Traditionen, Utopien, Dekonstruktionen - die Sozialstaatskonzepte des 'Ostblocks' (1945-1990)

The welfare state concepts in Eastern Europe under state socialism (1945-1990) were based on the conviction that only the state was responsible for solving all social problems. The 'bourgeois' manners of individual care were substituted by general measures in the field of labour- and family politics, as well as urban development. The experience showed however that this way of substitution was an illusion, because certain target groups were still in need of help (for example ill or handicapped children and adults, elderly people etc). Nevertheless, most of the Eastern European countries - with the exception of Yugoslavia - decided to abolish the existing forms of professional social work and the training for social workers. Instead, they invented 'surrogate structures' to manage the care for the 'needy': Various institutions and occupational groups (schools, hospitals and ambulances, employees groups etc.) took over the tasks of social workers and were trained to fulfil this as a kind of 'social practice'. Therefore, it is wrong to claim that social work was completely abolished under state socialism, But: as social work 'as such' did not exist any longer, it is more reasonable to speak of welfare state concepts, including social policy on one hand, and non- or paraprofessional social practice on the other. To characterize the effect of these welfare state concepts three parameter of interpretation seem to be useful: 'traditions', 'visions', and 'deconstructions' - embedded in a system of repression as well as incentives. Traditions: The huge 'social laboratory' that was installed was not a totally new one - it still carried on the heritage of the bygone: some bourgeois traces as well as elements out of the fascist heritage and -last but not least - the traditions of their own socialist movement. Visions: The socialist traditions included visions of social justice, the creation of a 'new mankind', a classless society, the end of exploitation and a peaceful living together of all people. Although the 'real existing socialism' has destroyed most of these visions, the power of these utopian ideas has outshined a lot of the every day’s misfortune and injustice for quite a long time. Deconstructions: The term of 'deconstruction' has a threefold meaning: the deconstruction of professional welfare, the deconstruction - in the sense of reinterpretation - of the socialist ideals such as social justice and social security, making an instrument of inclusion and exclusion out of it. And the deconstruction that is necessary to free the history of social work under state socialism from the prejudices and distorting practices, from both sides, the east and the west. In the contribution these three parameter of interpretation are applied on the following issues: The gaps in the 'overall system' of social security; working morale and education for work; mass organisations as an instrument of egalitarianism and general prevention; de-professionalisation by 'surrogating' social work; the 'transparent client'; church as refuge or 'state organ'; women’s politics as bio-politics.

Neighbourhoods Mobilise the Troops - Community Organising, Violence and Governmentality

The article reflects on the difficult relation between community work against domestic violence and local crime prevention under the conditions of the neoliberal state that cuts down on social benefits and promotes self-help, active citizenship and self-responsibility instead while at the same time restoring the punishing state with its strict regime of law-and-order. The author describes a project Tarantula - she started herself while being a social worker in Hamburg, Germany. Tarantula was aimed at strengthening social networks and the neighbours' willingness to get involved in favour of affected women. Although conceptualized as an emancipatory approach referring to community organizing in the tradition of social movements it is questionable whether and how this can really work in the current situation. At present, the field of crime control is being reconfigured as a result of political and administrative decisions, which, for their part, are based on a new structure of social relations and cultural attitudes. The demolition of the 'welfare state' means the re-coding of the security policy that facilitates the development of interventionist techniques that govern and control individuals through their own ability to act.

Das Museum lebt? Der Diskurs der Vernetzung im virtuellen Raum

Kunstwerke sowie ihre Präsentation und Vermittlung werden zunehmend von digitalen Technologien unterstützt. Virtuelle Ausstellungen, Internet-Projekte und komplexe Datenarchive stellen das Kunstwerk in einen medialen Kontext, der weit über das Moment einer technischen Reproduzierbarkeit hinausgeht. Das allgegenwärtige Konzept der Vernetzung dynamisiert Kunst, ihre Rezipienten und Ausstellungsorte. Die Beziehungen zwischen diesen Feldern werden mit Hilfe physiologischer Metaphern definiert und visualisiert. Frühere Speicher und Archive geraten in einen prozessualen Sog, in dem alles fluktuiert, sich kurzweilig verknüpft, auflöst, und in permanente Dialoge mit seiner Umgebung tritt - das virtuelle Museum gerät in aktuellen Standortbestimmungen in die definitorische Nähe des Künstlichen Lebens.