Binding kinetics drive G protein subtype selectivity at the ß1-adrenergic receptor.

G protein-coupled receptors (GPCRs) bind to different G protein α-subtypes with varying degrees of selectivity. The mechanism by which GPCRs achieve this selectivity is still unclear. Using 13C methyl methionine and 19F NMR, we investigate the agonist-bound active state of ß1AR and its ternary complexes with different G proteins in solution. We find the receptor in the ternary complexes adopts very similar conformations. In contrast, the full agonist-bound receptor active state assumes a conformation differing from previously characterised activation intermediates or from ß1AR in ternary complexes. Assessing the kinetics of binding for the agonist-bound receptor with different G proteins, we find the increased affinity of ß1AR for Gs results from its much faster association with the receptor. Consequently, we suggest a kinetic-driven selectivity gate between canonical and secondary coupling which arises from differential favourability of G protein binding to the agonist-bound receptor active state.

The right to live independently and be included in the community.

The segregation and isolation of people with disabilities are global problems, rooted in legislation and policy, social norms and traditional practices. The right to live independently and be included in the community, contained in article 19 of the United Nations Convention on the Rights of Persons with Disabilities, was created to combat the phenomenon of institutionalization and to spur efforts towards its eventual eradication. This essay offers a commentary on article 19, drawing on its drafting history, on the interpretation provided by the responsible UN body and on the efforts by that body to monitor and encourage compliance. It emphasizes the extent of the transformation required to realize the full ambition of the article and the need for cooperation across UN treaty bodies.

Legal capacity, mental capacity and supported decision-making: Report from a panel event.

Against a backdrop of the UN Convention on the Rights of Persons with Disabilities having been in place for over a decade, discussions about legal capacity, the relevance of mental capacity and the shift to supported decision-making, continue to develop. A panel event was held at the King's Transnational Law Summit in 2018 with the aim of understanding the contours of the dialogue around these issues. This paper presents the contributions of the panel members, a summary of the discussion that took place and a synthesis of the views expressed. It suggests that divergent conclusions in this area turn on disagreements about: the consequences of sometimes limiting legal capacity for people with mental disabilities; the emphasis placed on particular values; the basis for mental capacity assessments; and the scope for supported decision-making. It also highlights the connection between resources, recognition and freedoms for people with mental disabilities, and therefore the issues that arise when discussion in this area is limited to legal capacity in the context of decision-making.

Violence and abuse against people with disabilities: A comparison of the approaches of the European Court of Human Rights and the United Nations Committee on the Rights of Persons with Disabilities.

This paper explores how, and how effectively, two systems of international law have addressed exploitation, violence and abuse of people with mental disabilities. The two international systems reviewed were the Council of Europe's European Court of Human Rights and the United Nations Committee on the Rights of Persons with Disabilities. The two issues dealt with are (a) forced institutionalisation and denial of community-based services and (b) medically-sanctioned treatment as abuse or violence. The paper offers a comparative analysis of the way in which the two bodies have dealt with exploitation, violence and abuse of people with disabilities, and offers recommendations as to how the two bodies could adjust their approaches to come into closer alignment.

Human rights violations of people with mental and psychosocial disabilities: an unresolved global crisis.

This report reviews the evidence for the types of human rights violations experienced by people with mental and psychosocial disabilities in low-income and middle-income countries as well as strategies to prevent these violations and promote human rights in line with the UN Convention on the Rights of Persons with Disabilities (CRPD). The article draws on the views, expertise, and experience of 51 people with mental and psychosocial disabilities from 18 low-income and middle-income countries as well as a review of English language literature including from UN publications, non-governmental organisation reports, press reports, and the academic literature.