Stochastic model for the CheY-P molarity in the neighbourhood of E. coli flagella motors

E.coli serves as prototype for the study of peritrichous enteric bacteria that perform runs and tumbles alternately. Bacteria run forward as a result of the counterclockwise (CCW) rotation of their flagella bundle and perform tumbles when at least one of their flagella rotates clockwise (CW), moving away from the bundle. The flagella are hooked to molecular rotary motors of nanometric diameter able to make transitions between CCW and CW rotations that last up to one hundredth of a second. At the same time, flagella move or rotate the bacteria's body microscopically during lapses that range between a tenth and ten seconds. We assume that the transitions between CCW and CW rotations occur solely by fluctuations of CheY-P molarity in the presence of two threshold values, and that a veto rule selects the run or tumble motions. We present Langevin eqs for the CheY-P molarity in the vicinity of each molecular motor. This model allows to obtain the run- or tumble-time distribution as a linear combination of decreasing exponentials that is a function of the steady molarity of CheY-P in the neighbourhood of the molecular motor, which fits experimental data. In turn, if the internal signaling system is unstimulated, we show that the runtime distributions reach power-law behaviour, a characteristic of self-organized systems, in some time range and, afterwards, exponential cutoff. In addition, our model explains without any fitting parameters the ultrasensitivity of the flagella motors as a function of the steady state of CheY-P molarity. In addition, we show that the tumble bias for peritrichous bacterium has a similar sigmoid-shape to the CW bias, although shifted to lower concentrations when the flagella number increases. Thus, the increment in the flagella number allows lower operational values for each motor increasing amplification and robustness of the chemotatic pathway.Comment: 13 pages, 7 figure

The Shocking Impact of Corporate Scandal on Directors\u27 and Officers\u27 Liability

Directors and officers liability (hereinafter D&O) serves as a deterrent to corporate wrongdoing. Recent cycles of corporate scandal have impacted the tools used to manage the risk that D&O liability creates. The impact of these scandals is a shock, which is a sudden event that alters the market profoundly. Market alteration has counter intuitively resulted in increased availability of D&O insurance at a lower price, despite an increase in D&O liability. With increased D&O coverage offerings at lower costs, the market has become soft, making coverage readily available. Carriers are competing for insureds and there is now a risk of undermining the deterrent effect that D&O liability provides. This paper explores whether D&O liability\u27s deterrent effect has been jeopardized in this soft D&O insurance marke

What makes SMEs more likely to collaborate? Analysing the role of regional policy

The last twenty years have witnessed the diffusion of regional innovation policies supporting networks of innovators. The underlying aim of these policies is to encourage firms, particularly SMEs, to undertake collaborations with organisations possessing complementary knowledge. Focusing on a set of SMEs that have participated, over time, in several innovation networks funded by the same regional government, the paper investigates how their relationships have evolved with respect to the following aspects: (i) reiteration of pre-existing relationships as opposed to experimentation of new relationships; (ii) collaboration with organisations possessing complementary rather than similar knowledge and competencies; (iii) creation of local relationships rather than experimentation of extra-local collaborations; (iv) reliance upon intermediaries to connect with other organisations. Our findings reveal that the involvement in these policy-supported networks changed the firms’ relational patterns, leading them to collaborate with a wider variety of agents than those with whom they were linked before the policies. Sectoral heterogeneity had a negative effect on the probability to collaborate, while co-localisation increased the likelihood to collaborate. Mutual involvement with intermediaries also had a positive effect. However, in the case of firm-to-university relationships only specialized intermediaries were likely to perform a positive role and, therefore, encourage networking

Stereoselective synthesis of allele-specific BET inhibitors

Developing stereoselective synthetic routes that are efficient and cost-effective is important to allow easy access to biologically active molecules. Our previous syntheses of allele-selective bumped inhibitors of the Bromo and Extra-Terminal (BET) bromodomain proteins, Brd2, Brd3, Brd4 and BrdT, required a wasteful, late-stage alkylation step and expensive chiral separation. To circumvent these limitations, we developed a route based on stereocontrolled alkylation of an aspartic acid derivative that was used in a divergent, racemisation-free protocol to yield structurally diverse and enantiopure triazolodiazepines. With this approach, we synthesized bumped thienodiazepine-based BET inhibitor, ET-JQ1-OMe, in five steps and 99% ee without the need for chiral chromatography. Exquisite selectivity of ET-JQ1-OMe for Leu-Ala and Leu-Val mutants over wild-type bromodomain was confirmed by isothermal titration calorimetry and X-ray crystallography. Our new approach provides unambiguous chemical evidence for the absolute stereochemistry of the active, allele-specific BET inhibitor and a viable route that will facilitate wider access to this compound class

R&D policy instruments – a critical review of what we do and don’t know

In recent years, the term ‘policy instrument’ has been used more frequently with regard to R&D policy and innovation policy. What does this term mean? Where did it come from? What do we know about it, both with regard to the general field of policy studies but also in the specific context of R&D policy? This article examines the development of the notion of policy instruments as part of a body of research known as ‘policy design’. Over the last 50 years, there has been substantial progress in setting policy design on a more systematic basis, with the development of established concepts and analytical frameworks, including various taxonomies of policy instruments. However, with just a few exceptions, this body of research seems to have had little impact in the world of R&D policy. The paper reviews the literature on R&D policy instruments. It identifies a number of challenges for R&D policy instruments in the light of four transitions – the shift from linear to systemic thinking about R&D and innovation, the shift from national governments to multi-level governance, the shift from individual actors to collaborations and networks, and the shift from individual policies to policy mixes. It sets out a research agenda for the study of R&D policy instruments, before ending with a number of conclusions