Need and value of targeted immunosuppressive therapy in giant cell arteritis

Despite the heterogeneity of the giant cell arteritis (GCA) at the level of clinical manifestations and the cellular and molecular players involved in its pathogenesis, GCA is still treated with standardised regimens largely based on glucocorticoids (GC). Long-term use of high dosages of GC as required in GCA are associated with many clinically relevant side effects. In the recent years, the interleukin-6 receptor blocker tocilizumab has become available as the only registered targeted immunosuppressive agent in GCA. However, immunological heterogeneity may require different pathways to be targeted in order to achieve a clinical, immunological and vascular remission in GCA. The advances in the targeted blockade of various molecular pathways involved in other inflammatory and autoimmune diseases have catalyzed the research on targeted therapy in GCA. This article gives an overview of the studies with targeted immunosuppressive treatments in GCA, with a focus on their clinical value, including their effects at the level of vascular inflammation

DNA looping by FokI: the impact of twisting and bending rigidity on protein-induced looping dynamics

Protein-induced DNA looping is crucial for many genetic processes such as transcription, gene regulation and DNA replication. Here, we use tethered-particle motion to examine the impact of DNA bending and twisting rigidity on loop capture and release, using the restriction endonuclease FokI as a test system. To cleave DNA efficiently, FokI bridges two copies of an asymmetric sequence, invariably aligning the sites in parallel. On account of the fixed alignment, the topology of the DNA loop is set by the orientation of the sites along the DNA. We show that both the separation of the FokI sites and their orientation, altering, respectively, the twisting and the bending of the DNA needed to juxtapose the sites, have profound effects on the dynamics of the looping interaction. Surprisingly, the presence of a nick within the loop does not affect the observed rigidity of the DNA. In contrast, the introduction of a 4-nt gap fully relaxes all of the torque present in the system but does not necessarily enhance loop stability. FokI therefore employs torque to stabilise its DNA-looping interaction by acting as a ‘torsional’ catch bond

Governance Regime Factors Conducive to Innovation Uptake in Urban Water Management: Experiences from Europe

Innovative ways to manage the urban water cycle are required to deal with an ageing drinking and waste water infrastructure and new societal imperatives. This paper examines the influence of water governance in enabling transformations and technological innovation uptake in urban water management. A governance assessment framework is developed and applied in three case-studies, examining different scales and types of innovations used to tackle challenges in European urban water management. The methodology combines documentary analysis and interviews to reconstruct historical storylines of the shift in the water governance of urban water management for each site. The research provides detailed empirical observations on the factors conducive to innovation uptake at the local level. Critical governance factors such as commitment to compromise, the necessity to build political support, and the role of "entrepreneurs" and coalitions are highlighted. The paper also explores the role of discursive strategies and partnership design, as well as that of regulative, economic and communicative instruments, in creating barriers and opportunities to initiate and secure change. A number of recommendations targeted at innovators and water managers are presented in the conclusio

Systems analysis approach to the design of efficient water pricing policies under the EU Water Framework Directive

Economic theory suggests that water pricing can contribute to efficient management of water scarcity. The European Union (EU) Water Framework Directive (WFD) is a major legislative effort to introduce the use of economic instruments to encourage efficient water use and achieve environmental management objectives. However, the design and implementation of economic instruments for water management, including water pricing, has emerged as a challenging aspect of WFD implementation. This study demonstrates the use of a systems analysis approach to designing and comparing two economic approaches to efficient management of groundwater and surface water given EU WFD ecological flow requirements. Under the first approach, all wholesale water users in a river basin face the same volumetric price for water. This water price does not vary in space or in time, and surface water and groundwater are priced at the same rate. Under the second approach, surface water is priced using a volumetric price, while groundwater use is controlled through adjustments to the price of energy, which is assumed to control the cost of groundwater pumping. For both pricing policies, optimization is used to identify optimal prices, with the objective of maximizing welfare while reducing human water use in order to meet constraints associated with EU WFD ecological and groundwater sustainability objectives. The systems analysis approach demonstrates the successful integration of economic, hydrologic, and environmental components into an integrated framework for the design and testing of water pricing policies. In comparison to the first pricing policy, the second pricing policy, in which the energy price is used as a surrogate for a groundwater price, shifts a portion of costs imposed by higher water prices from low-value crops to high-value crops and from small urban/domestic locations to larger locations. Because growers of low-value crops will suffer the most from water price increases, the use of energy costs to control groundwater use offers the advantage of reducing this burden.The authors would like to thank the Danish Research School of Water Resources (FIVA) for financial support. Three anonymous reviewers made helpful suggestions that were incorporated into the revised version.Riegels, N.; Pulido-Velazquez, M.; Doulgeris, C.; Sturm, V.; Jensen, R.; Moller, F.; Bauer-Gottwein, P. (2013). Systems analysis approach to the design of efficient water pricing policies under the EU Water Framework Directive. Journal of Water Resources Planning and Management. 139(5):574-582. doi:10.1061/(ASCE)WR.1943-5452.0000284S574582139