New inhibitor targeting human transcription factor HSF1: effects on the heat shock response and tumour cell survival.

© The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected] Nuria Vilabo, Alba Bore, Francisco Martin-Saavedra, Melanie Bayford, Natalie Winfield, Stuart Firth-Clark, Stewart B. Kirton, and Richard Voellmy, 'New inhibitor targeting human transcription factor HSF1: effects on the heat shock response and tumor cell survival', Nucleic Acids Research, 2017, 1, doi: 10.1093/nar/gkx194Comparative modeling of the DNA-binding domain of human HSF1 facilitated the prediction of possible binding pockets for small molecules and definition of corresponding pharmacophores. In silico screening of a large library of lead-like compounds identified a set of compounds that satisfied the pharmacophoric criteria, a selection of which compounds was purchased to populate a biased sublibrary. A discriminating cell-based screening assay identified compound 001, which was subjected to systematic analysis of structure–activity relationships, resulting in the development of compound 115 (IHSF115). IHSF115 bound to an isolated HSF1 DNAbinding domain fragment. The compound did not affect heat-induced oligomerization, nuclear localization and specific DNA binding but inhibited the transcriptional activity of human HSF1, interfering with the assembly of ATF1-containing transcription complexes. IHSF115 was employed to probe the human heat shock response at the transcriptome level. In contrast to earlier studies of differential regulation in HSF1-na¨ıve and -depleted cells, our results suggest that a large majority of heat-induced genes is positively regulated by HSF1. That IHSF115 effectively countermanded repression in a significant fraction of heat-repressed genes suggests that repression of these genes is mediated by transcriptionally active HSF1. IHSF115 is cytotoxic for a variety of human cancer cell lines, multiplemyeloma lines consistently exhibiting high sensitivity.Peer reviewedFinal Published versio

Matters of Trust as Matters of Attachment Security

I argue for an account of the vulnerability of trust, as a product of our need for secure social attachments to individuals and to a group. This account seeks to explain why it is true that, when we trust or distrust someone, we are susceptible to being betrayed by them, rather than merely disappointed or frustrated in our goals. What we are concerned about in matters of trust is, at the basic level, whether we matter, in a non-instrumental way, to that individual, or to the group of which they are a member. We have this concern as a result of a drive to form secure social attachments. This makes us vulnerable in the characteristic way of being susceptible to betrayal, because how the other acts in such matters can demonstrate our lack of worth to them, or to the group, thereby threatening the security of our attachment, and eliciting the reactive attitudes characteristic of betrayal

WHITE HEAT: racism, under-achievement and white working-class boys

The article examines students' experience of inner-city education in one of England’s most disadvantaged areas. In particular, we reflect on the views of white working class boys, a group that has recently been identified by policy-makers and the media as especially at risk of educational failure. These young people recognise the educational disadvantage they face on a daily basis, made explicit in a tangible lack of resourcing and institutionalised through selection systems (like banding and setting). These injustices are re-worked through the students' perspectives, taking cues from national and community racist discourses of white victimhood. In this way the white students view their educational and class disadvantage as a Ôrace' issue. We conclude that this is an important but largely unrecognised way in which racism continues to work through a system that, despite changes in rhetoric, refuses to engage with the reality of racism as a deeply rooted and defining characteristic of the education system

Spatial dynamics, thermalization, and gain clamping in a photon condensate

We study theoretically the effects of pump-spot size and location on photon condensates. By exploring the inhomogeneous molecular excitation fraction, we make clear the relation between spatial equilibration, gain clamping and thermalization in a photon condensate. This provides a simple understanding of several recent experimental results. We find that as thermalization breaks down, gain clamping is imperfect, leading to "transverse spatial hole burning" and multimode condensation. This opens the possibility of engineering the gain profile to control the condensate structure.Comment: Further extended, including new figures. Now 10 figure

Do corporations have a duty to be trustworthy?

Since the global financial crisis in 2008, corporations have faced a crisis of trust, with growing sentiment against ‘elites and ‘big business’ and a feeling that ‘something ought to be done’ to re-establish public regard for corporations. Trust and trustworthiness are deeply moral significant. They provide the ‘glue or lubricant’ that begets reciprocity, decreases risk, secures dignity and respect, and safeguards against the subordination of the powerless to the powerful. However, in deciding how to restore trust, it is difficult to determine precisely what should be done, by whom, and who will bear the cost, especially if any action involves a risk to overall market efficiency and corporate profitability. The paper explores whether corporations have a moral duty to be trustworthy, to bear the cost of being so and thus contribute to resolving the current crisis of trust. It also considers where the state and other social actors have strong reason to protect and enforce such moral rights, while acknowledging that other actors have similar obligations to be trustworthy. It outlines five ‘salient factors’ that trigger specific rights to trustworthiness and a concomitant duty on corporations to be trustworthy: market power, subordination (threat and intimidation), the absence of choice, the need to preserve systemic trust, and corporate political power which might undermine a state’s legitimacy. Absent these factors and corporations do not have a general duty to be trustworthy, since a responsible actor in fair market conditions should be able to choose between the costs and benefits of dealing with generally trustworthy corporations

Thermalization and breakdown of thermalization in photon condensates

The authors acknowledge financial support from EPSRC program “TOPNES” (Grant No. EP/I031014/1) and EPSRC (Grant No. EP/G004714/2). P.G.K. acknowledges support from EPSRC (Grant No. EP/M010910/1).We examine in detail the mechanisms behind thermalization and Bose-Einstein condensation (BEC) of a gas of photons in a dye-filled microcavity. We derive a microscopic quantum model, based on that of a standard laser, and show how this model can reproduce the behavior of recent experiments. Using the rate-equation approximation of this model, we show how a thermal distribution of photons arises. We go on to describe how the nonequilibrium effects in our model can cause thermalization to break down as one moves away from the experimental parameter values. In particular, we examine the effects of changing cavity length, and of altering the vibrational spectrum of the dye molecules. We are able to identify two measures which quantify whether the system is in thermal equilibrium. Using these, we plot “phase diagrams” distinguishing BEC and standard lasing regimes. Going beyond the rate-equation approximation, our quantum model allows us to investigate both the second-order coherence g(2) and the linewidth of the emission from the cavity. We show how the linewidth collapses as the system transitions to a Bose condensed state, and compare the results to the Schawlow-Townes linewidth.Publisher PDFPeer reviewe