Organizational responses to a changing aid environment: the German Agency for Technical Cooperation (GTZ)

As a major European donor, German government development assistance faces a series of challenges. Recent political changes have raised expectations for demonstrable health outcomes as a result of German development assistance; there has been a deepened commitment to collaboration with other bilateral and multilateral donors; and partner countries are increasingly open to new approaches to development. German development assistance also reflects a new ethos of partnership and the shift to programmatic and sector based development approaches. At the same time, its particular organizational structure and administrative framework highlight the extent of structural and systems reforms required of donors by changing development relationships, and the tensions created in responding to these. This paper examines organizational changes within the German Agency for Technical Cooperation (Deutsche Gesellschaft fur Technische Zusammenarbeit) (GTZ), aimed at increasing its Regional, Sectoral, Managerial and Process competence as they affect health and related sectors. These include the decentralization of GTZ, the trend to integration of projects, the increasing focus on policy and health systems reform, increased inter-sectoral collaboration, changes in recruitment and training, new perspectives in planning and evaluation and the introduction of a quality management programme. Copyright (C) 2002 John Wiley Sons, Ltd.

The AF-1 Domain of the Orphan Nuclear Receptor NOR-1 Mediates Trans-activation, Coactivator Recruitment, and Activation by the Purine Anti-metabolite 6-Mercaptopurine

NOR-1/NR4A3 is an orphan member of the nuclear hormone receptor superfamily. NOR-1 and its close relatives Nurr1 and Nur77 are members of the NR4A subgroup of nuclear receptors. Members of the NR4A subgroup are induced through multiple signal transduction pathways. They have been implicated in cell proliferation, differentiation, T-cell apoptosis, chondrosarcomas, neurological disorders, inflammation, and atherogenesis. However, the mechanism of transcriptional activation, coactivator recruitment, and agonist-mediated activation remain obscure. Hence, we examined the molecular basis of NOR-1-mediated activation. We observed that NOR-1 trans-activates gene expression in a cell- and target-specific manner; moreover, it operates in an activation function (AF)-1-dependent manner. The N-terminal AF-1 domain delimited to between amino acids 1 and 112, preferentially recruits the steroid receptor coactivator (SRC). Furthermore, SRC-2 modulates the activity of the AF-1 domain but not the C-terminal ligand binding domain (LBD). Homology modeling indicated that the NOR-1 LBD was substantially different from that of hRORbeta, a closely related AF-2-dependent receptor. In particular, the hydrophobic cleft characteristic of nuclear receptors was replaced with a very hydrophilic surface with a distinct topology. This observation may account for the inability of this nuclear receptor LBD to efficiently mediate cofactor recruitment and transcriptional activation. In contrast, the N-terminal AF-1 is necessary for cofactor recruitment and can independently conscript coactivators. Finally, we demonstrate that the purine anti-metabolite 6-mercaptopurine, a widely used antineoplastic and anti-inflammatory drug, activates NOR-1 in an AF-1-dependent manner. Additional 6-mercaptopurine analogs all efficiently activated NOR-1, suggesting that the signaling pathways that modulate proliferation via inhibition of de novo purine and/or nucleic acid biosynthesis are involved in the regulation NR4A activity. We hypothesize that the NR4A subgroup mediates the genotoxic stress response and suggest that this subgroup may function as sensors that respond to genotoxicity.