The Tissue-Specific Rep8/UBXD6 Tethers p97 to the Endoplasmic Reticulum Membrane for Degradation of Misfolded Proteins

The protein known as p97 or VCP in mammals and Cdc48 in yeast is a versatile ATPase complex involved in several biological functions including membrane fusion, protein folding, and activation of membrane-bound transcription factors. In addition, p97 plays a central role in degradation of misfolded secretory proteins via the ER-associated degradation pathway. This functional diversity of p97 depends on its association with various cofactors, and to further our understanding of p97 function it is important that these cofactors are identified and analyzed. Here, we isolate and characterize the human protein named Rep8 or Ubxd6 as a new cofactor of p97. Mouse Rep8 is highly tissue-specific and abundant in gonads. In testes, Rep8 is expressed in post-meiotic round spermatids, whereas in ovaries Rep8 is expressed in granulosa cells. Rep8 associates directly with p97 via its UBX domain. We show that Rep8 is a transmembrane protein that localizes to the ER membrane with its UBX domain facing the cytoplasm. Knock-down of Rep8 expression in human cells leads to a decreased association of p97 with the ER membrane and concomitantly a retarded degradation of misfolded ER-derived proteasome substrates. Thus, Rep8 tethers p97 to the ER membrane for efficient ER-associated degradation

EPIdemiology of Surgery-Associated Acute Kidney Injury (EPIS-AKI) : Study protocol for a multicentre, observational trial

More than 300 million surgical procedures are performed each year. Acute kidney injury (AKI) is a common complication after major surgery and is associated with adverse short-term and long-term outcomes. However, there is a large variation in the incidence of reported AKI rates. The establishment of an accurate epidemiology of surgery-associated AKI is important for healthcare policy, quality initiatives, clinical trials, as well as for improving guidelines. The objective of the Epidemiology of Surgery-associated Acute Kidney Injury (EPIS-AKI) trial is to prospectively evaluate the epidemiology of AKI after major surgery using the latest Kidney Disease: Improving Global Outcomes (KDIGO) consensus definition of AKI. EPIS-AKI is an international prospective, observational, multicentre cohort study including 10 000 patients undergoing major surgery who are subsequently admitted to the ICU or a similar high dependency unit. The primary endpoint is the incidence of AKI within 72 hours after surgery according to the KDIGO criteria. Secondary endpoints include use of renal replacement therapy (RRT), mortality during ICU and hospital stay, length of ICU and hospital stay and major adverse kidney events (combined endpoint consisting of persistent renal dysfunction, RRT and mortality) at day 90. Further, we will evaluate preoperative and intraoperative risk factors affecting the incidence of postoperative AKI. In an add-on analysis, we will assess urinary biomarkers for early detection of AKI. EPIS-AKI has been approved by the leading Ethics Committee of the Medical Council North Rhine-Westphalia, of the Westphalian Wilhelms-University Münster and the corresponding Ethics Committee at each participating site. Results will be disseminated widely and published in peer-reviewed journals, presented at conferences and used to design further AKI-related trials. Trial registration number NCT04165369

Multilevel Democracy: A Comparative Perspective

Treating electoral accountability as a necessary institutional precondition of both input- and output-oriented democratic legitimacy, the chapter explores its realization in several variants of multilevel government. Whereas US “dual federalism” and German “joint-decision federalism” differ significantly in the allocation of governing powers and in coupling or decoupling of governing processes, they are highly effective in establishing the political accountability of governments to electorates on both levels. By contrast, both the EU and the European Monetary Union (EMU) lack a politically accountable government. And whereas EU legislation might draw upon the democratic legitimacy of national governments, the present EMU regime must be able to control and override the exercise of national governing powers by democratically accountable national governments

Strategies for knowledge acquisition in bionanotechnology

Discourses on convergent technologies claim that fields such as bionanotechnology are interdisciplinary and, therefore, require specific organizational forms, such as laboratories with researchers from many different disciplinary backgrounds. However, empirical investigations challenge the intrinsic interdisciplinarity of these emergent fields, and some analysts criticize the discourses as prescriptive. In order to investigate actual laboratory practices in bionanoscience, this article explores the dynamics of knowledge integration and the knowledge acquisition strategies of 10 research projects in two research specialities, namely biomolecular motors and lab-on-a-chip. The research shows that knowledge integration is, in fact, very asymmetrical: typically, a project will use materials and techniques from various disciplines at a standard level of know-how, but focus its research effort on the unique expertise of the home laboratory. Furthermore, projects use various strategies to acquire knowledge: interdisciplinary practices involving deep collaborations and exchanges between distinct disciplines at either the personal or institutional level are only one strategy to acquire knowledge and, indeed, not the most common. The majority of projects combine different strategies, including service collaboration, limited recruitment and in-house learning. These observations can be explained by a trade-off between the benefits of cognitive diversity set against the costs of team cohesion and learning