The Alzheimer's disease-linked protease BACE1 modulates neuronal IL-6 signaling through shedding of the receptor gp130

Background The protease BACE1 is a major drug target for Alzheimer's disease, but chronic BACE1 inhibition is associated with non-progressive cognitive worsening that may be caused by modulation of unknown physiological BACE1 substrates. Methods To identify in vivo-relevant BACE1 substrates, we applied pharmacoproteomics to non-human-primate cerebrospinal fluid (CSF) after acute treatment with BACE inhibitors. Results Besides SEZ6, the strongest, dose-dependent reduction was observed for the pro-inflammatory cytokine receptor gp130/IL6ST, which we establish as an in vivo BACE1 substrate. Gp130 was also reduced in human CSF from a clinical trial with a BACE inhibitor and in plasma of BACE1-deficient mice. Mechanistically, we demonstrate that BACE1 directly cleaves gp130, thereby attenuating membrane-bound gp130 and increasing soluble gp130 abundance and controlling gp130 function in neuronal IL-6 signaling and neuronal survival upon growth-factor withdrawal. Conclusion BACE1 is a new modulator of gp130 function. The BACE1-cleaved, soluble gp130 may serve as a pharmacodynamic BACE1 activity marker to reduce the occurrence of side effects of chronic BACE1 inhibition in humans

The Role of CO2-EOR for the Development of a CCTS Infrastructure in the North Sea Region: A Techno-Economic Model and Application

Scenarios of future energy systems attribute an important role to Carbon Capture, Transport, and Storage (CCTS) in achieving emission reductions. Using captured CO2 for enhanced oil recovery (CO2-EOR) can improve the economics of the technology. This paper examines the potential for CO2-EOR in the North Sea region. UK oil fields are found to account for 47% of the estimated additional recovery potential of 3739 Mbbl (1234 MtCO2 of storage potential). Danish and Norwegian fields add 28% and 25%, respectively. Based on a comprehensive dataset, the paper develops a unique techno-economic market equilibrium model of CO2 supply from emission sources and CO2 demand from CO2-EOR to assess implications for a future CCTS infrastructure. A detailed representation of decreasing demand for fresh CO2 for CO2-EOR operation is accomplished via an exponential storage cost function. In all scenarios of varying CO2 and crude oil price paths the assumed CO2-EOR potential is fully exploited. CO2-EOR does add value to CCTS operations but the potential is very limited and does not automatically induce long term CCTS activity. If CO2 prices stay low, little further use of CCTS can be expected after 2035

Once the shovel hits the ground : Evaluating the management of complex implementation processes of public-private partnership infrastructure projects with qualitative comparative analysis

Much attention is being paid to the planning of public-private partnership (PPP) infrastructure projects. The subsequent implementation phase – when the contract has been signed and the project ‘starts rolling’ – has received less attention. However, sound agreements and good intentions in project planning can easily fail in project implementation. Implementing PPP infrastructure projects is complex, but what does this complexity entail? How are projects managed, and how do public and private partners cooperate in implementation? What are effective management strategies to achieve satisfactory outcomes? This is the fi rst set of questions addressed in this thesis. Importantly, the complexity of PPP infrastructure development imposes requirements on the evaluation methods that can be applied for studying these questions. Evaluation methods that ignore complexity do not create a realistic understanding of PPP implementation processes, with the consequence that evaluations tell us little about what works and what does not, in which contexts, and why. This hampers learning from evaluations. What are the requirements for a complexity-informed evaluation method? And how does qualitative comparative analysis (QCA) meet these requirements? This is the second set of questions addressed in this thesis