Binary and Millisecond Pulsars at the New Millennium

We review the properties and applications of binary and millisecond pulsars. Our knowledge of these exciting objects has greatly increased in recent years, mainly due to successful surveys which have brought the known pulsar population to over 1300. There are now 56 binary and millisecond pulsars in the Galactic disk and a further 47 in globular clusters. This review is concerned primarily with the results and spin-offs from these surveys which are of particular interest to the relativity community.Comment: 59 pages, 26 figures, 5 tables. Accepted for publication in Living Reviews in Relativity (http://www.livingreviews.org

Improving Newborn Survival in Low-Income Countries: Community-Based Approaches and Lessons from South Asia

David Osrin and colleagues discuss the critical importance of reducing global neonatal mortality in developing countries and how community-based approaches can help

Student politics, teaching politics, black politics: an interview with Ansel Wong

Ansel Wong is the quiet man of British black politics, rarely in the limelight and never seeking political office. And yet his ‘career’ here – from Black Power firebrand to managing a multimillion budget as head of the Greater London Council’s Ethnic Minority Unit in the 1980s – spells out some of the most important developments in black educational and cultural projects. In this interview, he discusses his identification with Pan-Africanism, his involvement in student politics, his role in the establishment of youth projects and supplementary schools in the late 1960s and 1970s, and his involvement in black radical politics in London in the same period, all of which took place against the background of revolutionary ferment in the Third World and the world of ideas, and were not without their own internal class and ethnic conflicts

The role of ligand efficiency metrics in drug discovery

The judicious application of ligand or binding efficiencies, which quantify the molecular properties required to gain binding affinity for a drug target, is gaining traction in the selection and optimisation of fragments, hits, and leads. Retrospective analysis of recently marketed oral drugs shows that they frequently have highly optimised ligand efficiency values for their target. Optimising ligand efficiencies based on both molecular size and lipophilicity, when set in the context of the specific target, has the potential to ameliorate the molecular inflation that pervades current practice in medicinal chemistry, and to increase the developability of drug candidates

Structural Basis for Dual-Inhibition Mechanism of a Non-Classical Kazal-Type Serine Protease Inhibitor from Horseshoe Crab in Complex with Subtilisin

Serine proteases play a crucial role in host-pathogen interactions. In the innate immune system of invertebrates, multi-domain protease inhibitors are important for the regulation of host-pathogen interactions and antimicrobial activities. Serine protease inhibitors, 9.3-kDa CrSPI isoforms 1 and 2, have been identified from the hepatopancreas of the horseshoe crab, Carcinoscorpius rotundicauda. The CrSPIs were biochemically active, especially CrSPI-1, which potently inhibited subtilisin (Ki = 1.43 nM). CrSPI has been grouped with the non-classical Kazal-type inhibitors due to its unusual cysteine distribution. Here we report the crystal structure of CrSPI-1 in complex with subtilisin at 2.6 Å resolution and the results of biophysical interaction studies. The CrSPI-1 molecule has two domains arranged in an extended conformation. These two domains act as heads that independently interact with two separate subtilisin molecules, resulting in the inhibition of subtilisin activity at a ratio of 1:2 (inhibitor to protease). Each subtilisin molecule interacts with the reactive site loop from each domain of CrSPI-1 through a standard canonical binding mode and forms a single ternary complex. In addition, we propose the substrate preferences of each domain of CrSPI-1. Domain 2 is specific towards the bacterial protease subtilisin, while domain 1 is likely to interact with the host protease, Furin. Elucidation of the structure of the CrSPI-1: subtilisin (1∶2) ternary complex increases our understanding of host-pathogen interactions in the innate immune system at the molecular level and provides new strategies for immunomodulation