Total synthesis of the actinoallolides and a designed photoaffinity probe for target identification.

The actinoallolides are a family of polyketide natural products isolated from the bacterium Actinoallomurus fulvus. They show potent biological activity against trypanosomes, the causative agents of the neglected tropical diseases human African trypanosomiasis (sleeping sickness) and Chagas disease, while exhibiting no cytotoxicity against human cell lines. Herein, we give a full account of our strategy evolution towards the synthesis of this structurally unique class of 12-membered macrolides, which culminated in the first total synthesis of (+)-actinoallolide A in 20 steps and 8% overall yield. Subsequent late-stage diversification then provided ready access to the congeneric (+)-actinoallolides B-E. Enabled by this flexible and efficient endgame sequence, we also describe the design and synthesis of a photoaffinity probe based on actinoallolide A to investigate its biological mode of action. This will allow ongoing labelling studies to identify their protein binding target(s)

A Unified Total Synthesis of the Actinoallolides, a Family of Potent Anti-Trypanosomal Macrolides.

Trypanosoma protozoan parasites are the causative agents of Chagas disease and sleeping sickness, two neglected tropical diseases where there is an urgent need for improved treatments and the evaluation of promising drug leads like the actinoallolides. Enabled by the highly stereocontrolled aldol reactions of three chiral ketone building blocks, an efficient first total synthesis of the potent anti-trypanosomal macrolide (+)-actinoallolide A has been achieved in 17 steps and 8 % overall yield. Our convergent route features an adventurous ring-closing metathesis to form the requisite trisubstituted (8E)-alkene in the 12-membered macrolactone, followed by the controlled installation of the labile transannular hemiacetal. Late-stage diversification then provides ready access to the congeneric (+)-actinoallolides B-E

Preferred Basis in a Measurement Process

The effect of decoherence is analysed for a free particle, interacting with an environment via a dissipative coupling. The interaction between the particle and the environment occurs by a coupling of the position operator of the particle with the environmental degrees of freedom. By examining the exact solution of the density matrix equation one finds that the density matrix becomes completely diagonal in momentum with time while the position space density matrix remains nonlocal. This establishes the momentum basis as the emergent 'preferred basis' selected by the environment which is contrary to the general expectation that position should emerge as the preferred basis since the coupling with the environment is via the position coordinate.Comment: Standard REVTeX format, 10 pages of output. Accepted for publication in Phys. Rev

Discovery and evolution of primordial antibiotic resistance genes from soil microbes

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On the poverty of a priorism: technology, surveillance in the workplace and employee responses

Many debates about surveillance at work are framed by a set of a priori assumptions about the nature of the employment relationship that inhibits efforts to understand the complexity of employee responses to the spread of new technology at work. In particular, the debate about the prevalence of resistance is hamstrung from the outset by the assumption that all apparently non-compliant acts, whether intentional or not, are to be counted as acts of resistance. Against this background this paper seeks to redress the balance by reviewing results from an ethnographic study of surveillance-capable technologies in a number of British workplaces. It argues for greater attention to be paid to the empirical character of the social relations at work in and through which technologies are deployed and in the context of which employee responses are played out

The Claims Culture: A Taxonomy of Industry Attitudes

This paper presents an analysis of a familiar aspect of construction industry culture that we have dubbed 'the claims culture'. This is a culture of contract administration that lays a strong emphasis on the planning and management of claims. The principal elements of the analysis are two sets of distinctions. The first comprises economic and occupational orders, referring to two kinds of control that are exercised over the construction process; predicated respectively on economic ownership and occupational competence. The second refers to contrasting attitudes towards relationships and problem solving within these orders: respectively 'distributive' and 'integrative'. The concepts of economic and occupational order entail further sub-categories. The various attitudes associated with these categories and sub-categories are described. They are assessed as to their consequences for change initiatives in the industry

Searching for the Kuhnian moment : the Black-Scholes-Merton formula and the evolution of modern finance theory

The Black-Scholes-Merton formula has been put to widespread use by options traders because it provides a means of calculating the theoretically 'correct' price of stock options. Traders can therefore see whether the market price of stock options undervalues or overvalues them compared with their hypothetical Black-Scholes-Merton price, before choosing to buy or sell options accordingly. As a consequence of this close relationship between options pricing theory and options pricing practice, a strong performativity loop was activated, whereby market prices quickly converged on the hypothetical Black-Scholes-Merton prices following the dissemination of the formula. The theory has therefore had significant real-world effects, but how should we characterize the initial instinct to derive the theory from a philosophy of science perspective? The two books under review suggest that a Kuhnian reading of the advancement of scientific knowledge might well be the most appropriate. But, on closer inspection, it becomes clear that the publication of the Black-Scholes-Merton formula should not be seen as a Kuhnian moment with paradigm-shaping attributes. It is shown that, at most, the formula acts as an important exemplar which, via its use in the training of options pricing theorists and options pricing practitioners, reinforces the entrenchment of finance theory within the orthodox economics worldview

Towards 5G Software-Defined Ecosystems: Technical Challenges, Business Sustainability and Policy Issues

Techno-economic drivers are creating the conditions for a radical change of paradigm in the design and operation of future telecommunications infrastructures. In fact, SDN, NFV, Cloud and Edge-Fog Computing are converging together into a single systemic transformation termed “Softwarization” that will find concrete exploitations in 5G systems. The IEEE SDN Initiative1 has elaborated a vision, an evolutionary path and some techno-economic scenarios of this transformation: specifically, the major technical challenges, business sustainability and policy issues have been investigated. This white paper presents: 1) an overview on the main techno-economic drivers steering the “Softwarization” of telecommunications; 2) an introduction to the Open Mobile Edge Cloud vision (covered in a companion white paper); 3) the main technical challenges in terms of operations, security and policy; 4) an analysis of the potential role of open source software; 5) some use case proposals for proof-of-concepts; and 6) a short description of the main socio-economic impacts being produced by “Softwarization”. Along these directions, IEEE SDN is also developing of an open catalogue of software platforms, toolkits, and functionalities aiming at a step-by-step development and aggregation of test-beds/field-trials on SDNNFV- 5G