Synthetic chemical inducers and genetic decoupling enable orthogonal control of the rhaBAD promoter

External control of gene expression is crucial in synthetic biology and biotechnology research and applications, and is commonly achieved using inducible promoter systems. The E. coli rhamnose-inducible rhaBAD promoter has properties superior to more commonly-used inducible expression systems, but is marred by transient expression caused by degradation of the native inducer, L-rhamnose. To address this problem, 35 analogs of L-rhamnose were screened for induction of the rhaBAD promoter, but no strong inducers were identified. In the native configuration, an inducer must bind and activate two transcriptional activators, RhaR and RhaS. Therefore, the expression system was reconfigured to decouple the rhaBAD promoter from the native rhaSR regulatory cascade so that candidate inducers need only activate the terminal transcription factor RhaS. Re-screening the 35 compounds using the modified rhaBAD expression system revealed several promising inducers. These were characterised further to determine the strength, kinetics and concentration-dependence of induction; whether the inducer was used as a carbon source by E. coli; and the modality (distribution) of induction among populations of cells. L-Mannose was found to be the most useful orthogonal inducer, providing an even greater range of induction than the native inducer Lrhamnose, and crucially, allowing sustained induction instead of transient induction. These findings address the key limitation of the rhaBAD expression system, and suggest it may now be the most suitable system for many applications

John Lilburne and the Long Parliament

This piece reinterprets the career of the Leveller, John Lilburne, during the English Civil War, by re-examining the official sources pertaining to him, and the multitude of pamphlets written by himself and his enemies. The article recovers the chronology of Lilburne's story, by stripping away the layers of propaganda with which he later surrounded himself. It shows that he had powerful friends at Westminster, and that his tribulations were caused by political rivalries within Westminster rather than his development of a radical political theory. He is shown to have formed part of the Independent alliance during the mid-1640s, although his protected position was eventually imperilled by the fracturing of this group after the end of the first Civil War. The aim is to improve not just our understanding of Lilburne, but the complexity of parliamentarian politics during the 1640s

Steps in immunosuppression for renal transplantation

The authors provide a historical survey of the immunosuppressive agents that have been used to prevent allograft rejection. Attention is given to the expected effect of cyclosporin in kidney translations

Order and disorder in Europe: Parliamentary agents and Royalist thugs 1649-1650

After the execution of Charles I in 1649 a series of daring and desperate attempts were made on the lives of agents and ambassadors dispatched to continental Europe by the fledgling republic. This essay explores the evidence relating to these plots, and to the murders of Isaac Dorislaus and Anthony Ascham, in an attempt to show that the royalists responsible were not merely desperadoes seeking revenge for the murder of their king, but the employees and emissaries of prominent exiled courtiers. The complicity of Montrose, Cottington and Hyde in such conspiracy can be both documented and explained, in the context of the struggle for diplomatic recognition and financial assistance in the months of shock, outrage and uncertainty after the regicide. The concerns of diplomacy and high politics which lay behind these plots also helped to determine the reaction of European leaders, as it gradually became clear on whose side fortune smiled in Britain

Constituency campaigning at the 2015 general election

The context of the 2015 general election suggested that the electoral impact of parties’ constituency campaigns could vary as a consequence in particular of the relative unpopularity of the Liberal Democrats. Using data from a survey of election agents, this paper analyses how the main GB level political parties adapted the intensity of their constituency level campaign’s to ensure that to varying degrees they produced positive electoral payoffs. It further analyses the electoral effects of face-to-face campaigning and e-campaigning at constituency level and shows that while e-campaigning has grown in importance, face-to-face campaigning continues to deliver stronger electoral benefits. Overall, the 2015 election illustrated that intense constituency level campaigning continues to be electorally beneficial for all the parties, but that this was the election when the Conservative Party became genuinely effective in terms of the delivery of electoral payoffs.This research was funded by the Economic and Social Research Council (Grant No. ES/M007251/1

A role for peroxisome proliferator-activated receptors in the immunopathology of schistosomiasis?

Peroxisome proliferator-activated receptors (PPARs) have been demonstrated to have a role in immune regulation. In general, they are anti-inflammatory and promote Th2 type responses, and they are associated with the alternative activation of macrophages. Interestingly, helminth infections, such as the schistosome blood flukes that cause schistosomiasis, are characterised by a Th2 response and the accumulation of alternative activated macrophages. This would suggest that at some level, PPARs could have a role in the modulation of the immune response in schistosomiasis. This paper discusses possible areas where PPARs could have a role in this disease

Developments in the tools and methodologies of synthetic biology.

Synthetic biology is principally concerned with the rational design and engineering of biologically based parts, devices, or systems. However, biological systems are generally complex and unpredictable, and are therefore, intrinsically difficult to engineer. In order to address these fundamental challenges, synthetic biology is aiming to unify a body of knowledge from several foundational scientific fields, within the context of a set of engineering principles. This shift in perspective is enabling synthetic biologists to address complexity, such that robust biological systems can be designed, assembled, and tested as part of a biological design cycle. The design cycle takes a forward-design approach in which a biological system is specified, modeled, analyzed, assembled, and its functionality tested. At each stage of the design cycle, an expanding repertoire of tools is being developed. In this review, we highlight several of these tools in terms of their applications and benefits to the synthetic biology community