HIV-1 gp41 Core with Exposed Membrane-Proximal External Region Inducing Broad HIV-1 Neutralizing Antibodies

The membrane-proximal external region (MPER) of the HIV-1 gp41 consists of epitopes for the broadly cross-neutralizing monoclonal antibodies 2F5 and 4E10. However, antigens containing the linear sequence of these epitopes are unable to elicit potent and broad neutralizing antibody responses in vaccinated hosts, possibly because of inappropriate conformation of these epitopes. Here we designed a recombinant antigen, designated NCM, which comprises the N- and C-terminal heptad repeats that can form a six-helix bundle (6HB) core and the MPER domain of gp41. Two mutations (T569A and I675V) previously reported to expose the neutralization epitopes were introduced into NCM to generate mutants named NCM(TA), NCM(IV), and NCM(TAIV). Our results showed that NCM and its mutants could react with antibodies specific for 6HB and MPER of gp41, suggesting that these antigens are in the form of a trimer of heterodimer (i.e., 6HB) with three exposed MPER tails. Antigen with double mutations, NCM(TAIV), elicited much stronger antibody response in rabbits than immunogens with single mutation, NCM(TA) and NCM(IV), or no mutation, NCM. The purified MPER-specific antibodies induced by NCM(TAIV) exhibited broad neutralizing activity, while the purified 6HB-specific antibodies showed no detectable neutralizing activity. Our recombinant antigen design supported by an investigation of its underlying molecular mechanisms provides a strong scientific platform for the discovery of a gp41 MPER-based AIDS vaccine

Probing the Links between Political Economy and Non-Traditional Security: Themes, Approaches, and Instruments

This is a pre-print of an article published in International Politics. The definitive publisher-authenticated version of: Hameiri, Shahar, and Lee Jones. "Probing the links between political economy and non-traditional security: Themes, approaches and instruments." International Politics (2015), is available online at: http://dx.doi.org/10.1057/ip.2015.1In recent decades, the security agenda for states and international organisations has expanded dramatically to include a range of ‘non-traditional’, transnational security issues. It is often suggested that globalisation has been a key driver for the emergence or intensification of these problems, but, surprisingly, little sustained scholarly effort has been made to examine the link between responses to the new security agenda and the changing political economy. This curious neglect largely reflects the mutual blind-spots of the sub-disciplines of International Security Studies and International Political Economy, coupled with the dominance of approaches that tend to neglect economic factors. This special issue, which this article introduces, aims to overcome this significant gap. In particular, it focuses on three key themes: the broad relationship between security and the political economy; what is being secured in the name of security, and how this has changed; and how things are being secured – what modes of governance have emerged to manage security problems. In all of these areas, the contributions point to the crucial role of the state in translating shifting state-economy relations to new security definitions and practices

Fimbrin phosphorylation by metaphase Cdk1 regulates actin cable dynamics in budding yeast

Actin cables, composed of actin filament bundles nucleated by formins, mediate intracellular transport for cell polarity establishment and maintenance. We previously observed that metaphase cells preferentially promote actin cable assembly through cyclin-dependent kinase 1 (Cdk1) activity. However, the relevant metaphase Cdk1 targets were not known. Here we show that the highly conserved actin filament crosslinking protein fimbrin is a critical Cdk1 target for actin cable assembly regulation in budding yeast. Fimbrin is specifically phosphorylated on threonine 103 by the metaphase cyclin–Cdk1 complex, in vivo and in vitro. On the basis of conformational simulations, we suggest that this phosphorylation stabilizes fimbrin's N-terminal domain, and modulates actin filament binding to regulate actin cable assembly and stability in cells. Overall, this work identifies fimbrin as a key target for cell cycle regulation of actin cable assembly in budding yeast, and suggests an underlying mechanism