Interpreting the functional role of a novel interaction motif in prokaryotic sodium channels

Voltage-gated sodium channels enable the translocation of sodium ions across cell membranes and play crucial roles in electrical signaling by initiating the action potential. In humans, mutations in sodium channels give rise to several neurological and cardiovascular diseases, and hence they are targets for pharmaceutical drug developments. Prokaryotic sodium channel crystal structures have provided detailed views of sodium channels, which by homology have suggested potentially important functionally related structural features in human sodium channels. A new crystal structure of a full-length prokaryotic channel, NavMs, in a conformation we proposed to represent the open, activated state, has revealed a novel interaction motif associated with channel opening. This motif is associated with disease when mutated in human sodium channels and plays an important and dynamic role in our new model for channel activation

Structural model of the open-closed-inactivated cycle of prokaryotic voltage-gated sodium channels

In excitable cells, the initiation of the action potential results from the opening of voltage-gated sodium channels. These channels undergo a series of conformational changes between open, closed, and inactivated states. Many models have been proposed for the structural transitions that result in these different functional states. Here, we compare the crystal structures of prokaryotic sodium channels captured in the different conformational forms and use them as the basis for examining molecular models for the activation, slow inactivation, and recovery processes. We compare structural similarities and differences in the pore domains, specifically in the transmembrane helices, the constrictions within the pore cavity, the activation gate at the cytoplasmic end of the last transmembrane helix, the C-terminal domain, and the selectivity filter. We discuss the observed differences in the context of previous models for opening, closing, and inactivation, and present a new structure-based model for the functional transitions. Our proposed prokaryotic channel activation mechanism is then compared with the activation transition in eukaryotic sodium channels

Pediatric clinical trials: a US perspective

Matthew J Oelstrom,1 Margo L Hoover-Regan2 1Children’s Hospital of Wisconsin, Milwaukee, WI, USA; 2Division of Pediatric Hematology and Oncology, The University of Wisconsin School of Medicine and Public Health, Madison, WI, USA Background: Since the scientific revolution, systematic child-subject experimentation has evolved, with regard not only to scientific methodology but also to appreciation of the vulnerability of pediatric subjects. Permission-assent or informed consent policies serve to protect pediatric subjects. Unfortunately, child-subject and parent-surrogate understanding of research is not satisfactory. Methods: The PubMed, Essential Evidence Plus, and CINAHL Plus databases were searched for literature on informed consent, permission, and assent in pediatric clinical trials. Articles with an emphasis on the parents' and subjects' understanding of clinical trials were selected for review and summary. Results: Seventy unique articles satisfied the search criteria. Each article was reviewed thoroughly for information about the informed consent process, parent (and, in some cases, child-subject) understanding of the nature of specific pediatric clinical trials, and procedures used or proposed to improve understanding of clinical research by subjects and/or their parents. Conclusion: Many parent-surrogates and child-subjects do not adequately understand clinical research. Parents and children often fail to understand randomization, especially as it relates to the principle of clinical equipoise. Children have additional difficulty with the nature of placebos and with right to withdraw from research at any time. Future research should prospectively evaluate interventions such as "staged consent," public education, medical trainee education, and alternative information-delivery methods, which are not yet known to consistently affect understanding. Keywords: informed consent, permission-assent, subject understandin

Regionalism and diffusion revisited : from final design towards stages of decision-making

First published online 14 January 2016An emerging research programme on diffusion across regional international organisations (RIOs) proposes that decisions taken in one RIO affect decision-making in other RIOs. This work has provided a welcome corrective to endogenously-focused accounts of RIOs. Nevertheless, by focusing on the final design of policies and institutional arrangements, it has been conceptually overly narrow. This has led to a truncated understanding of diffusion’s impact and to an unjustified view of convergence as its primary outcome. Drawing on public policy and sociological research, we offer a conceptual framework that seeks to remedy these weaknesses by disaggregating the decision-making process on the ‘receiving’ side. We suggest that policies and institutional arrangements in RIOs result from three decision-making stages: problematisation (identification of something as a political problem), framing (categorisation of the problem and possible solutions), and scripting (design of final solutions). Diffusion can affect any combination of these stages. Consequently, its effects are more varied and potentially extensive than is currently recognised, and convergence and persistent variation in scripting are both possible outcomes. We illustrate our framework by re-evaluating research on dispute settlement institutions in the EEC, NAFTA, and SADC. We conclude by discussing its theoretical implications and the conditions that likely promote diffusion