A redox switch in angiotensinogen modulates angiotensin release.

Blood pressure is critically controlled by angiotensins, which are vasopressor peptides specifically released by the enzyme renin from the tail of angiotensinogen-a non-inhibitory member of the serpin family of protease inhibitors. Although angiotensinogen has long been regarded as a passive substrate, the crystal structures solved here to 2.1 Å resolution show that the angiotensin cleavage site is inaccessibly buried in its amino-terminal tail. The conformational rearrangement that makes this site accessible for proteolysis is revealed in our 4.4 Å structure of the complex of human angiotensinogen with renin. The co-ordinated changes involved are seen to be critically linked by a conserved but labile disulphide bridge. Here we show that the reduced unbridged form of angiotensinogen is present in the circulation in a near 40:60 ratio with the oxidized sulphydryl-bridged form, which preferentially interacts with receptor-bound renin. We propose that this redox-responsive transition of angiotensinogen to a form that will more effectively release angiotensin at a cellular level contributes to the modulation of blood pressure. Specifically, we demonstrate the oxidative switch of angiotensinogen to its more active sulphydryl-bridged form in the maternal circulation in pre-eclampsia-the hypertensive crisis of pregnancy that threatens the health and survival of both mother and child

Decolonising drugs in Asia : the case of cocaine in colonial India

This article examines a drugs trade in Asia that has been largely forgotten by historians and policy-makers: cocaine. It will briefly trace some of the contours of this commerce and the efforts to control it. It will also assess how successful these efforts were. The article is designed to contribute fresh perspectives on recent controversies in the historiography of drugs in Asia to argue that the agendas and agency of consumers are central to understanding why markets have formed there for psychoactive substances in the modern period

Remembering probation in Scotland

Set within the contexts of probation’s upcoming centenary in Scotland (in 2005) and the current debate about the future of criminal justice social work in Scotland (and probation in England and Wales), this article provides an account of the early history of probation in Scotland, focussing on the rarely discussed period between 1905 and 1968. Following Nellis’s (2001) injunction to develop a ‘historically tutored memory’ as a defence against the narrowing of our visions for the future, and drawing on Vanstone’s (2004) recent work on the history of the service in England and Wales, the article pieces together and seeks to understand a significant change in Scottish probation’s core identity and purpose from providing supervision as an alternative to punishment to providing ‘treatment’ as a means of reforming offenders. In the concluding discussion, the article briefly summarises the subsequent move towards a welfare-oriented approach after 1968 and, more recently the drift towards public protection as an overarching purpose (Robinson and McNeill, 2004). The article concludes that the current debate in Scotland should shift from ‘second order’ questions around organizational arrangements to ‘first order’ questions around which aspects of these various purposes and identities should endure in the 21st century