Exploiting transient protein states for the design of small-molecule stabilizers of mutant p53

The destabilizing p53 cancer mutation Y220C creates an extended crevice on the surface of the protein that can be targeted by small-molecule stabilizers. Here, we identify different classes of small molecules that bind to this crevice and determine their binding modes by X-ray crystallography. These structures reveal two major conformational states of the pocket and a cryptic, transiently open hydrophobic subpocket that is modulated by Cys220. In one instance, specifically targeting this transient protein state by a pyrrole moiety resulted in a 40-fold increase in binding affinity. Molecular dynamics simulations showed that both open and closed states of this subsite were populated at comparable frequencies along the trajectories. Our data extend the framework for the design of high-affinity Y220C mutant binders for use in personalized anticancer therapy and, more generally, highlight the importance of implementing protein dynamics and hydration patterns in the drug-discovery process

Quantitative assessment of paravalvular regurgitation following transcatheter aortic valve replacement

Paravalvular aortic regurgitation (PAR) following transcatheter aortic valve implantation (TAVI) is well acknowledged. Despite improvements, echocardiographic measurement of PAR largely remains qualitative. Cardiovascular magnetic resonance (CMR) directly quantifies AR with accuracy and reproducibility. We compared CMR and transthoracic echocardiography (TTE) analysis of pre-operative and post-operative aortic regurgitation in patients undergoing both TAVI and surgical aortic valve replacement (AVR).Gareth Crouch, Phillip J Tully, Jayme Bennetts, Ajay Sinhal, Craig Bradbrook, Amy L Penhall, Carmine G De Pasquale, Robert A Baker, and Joseph B Selvanayaga

Improving energy efficiency in private rented housing : what makes landlords act?

The private rented sector in England contains some of the least energy efficient properties in the country and houses more vulnerable households than any other sector. Occupants endure dangerously cold homes and fuel poverty but have no direct influence over the energy performance of their homes. The choices that occupants make regarding energy are constrained by the material characteristics of a property: something only the landlord can alter. Enduringly poor conditions in the sector indicate that an initiative that convinces landlords of the benefits of improving energy efficiency remains elusive. Based on a review of existing research and 30 interviews with landlords, this paper identifies factors which deter landlords from acting to improve energy efficiency. Factors include lack of knowledge regarding the consequences of energy inefficiency and possible solutions, the absence of direct financial incentives (the principal–agent problem), local housing market and cultural factors. It also identifies a number of motivating factors that may encourage landlords to invest in energy efficiency. It is argued that policies to tackle energy inefficiency in the sector should take account of these factors in order to improve effectiveness. Keywords Private rented sector, Domestic energy efficiency, Principal–agent, The Green Deal, Private landlords, Split incentiv

Human influence on climate in the 2014 southern England winter floods and their impacts

A succession of storms reaching Southern England in the winter of 2013/2014 caused severe floods and £451 million insured losses. In a large ensemble of climate model simulations, we find that, as well as increasing the amount of moisture the atmosphere can hold, anthropogenic warming caused a small but significant increase in the number of January days with westerly flow, both of which increased extreme precipitation. Hydrological modelling indicates this increased extreme 30-day-average Thames river flows, and slightly increased daily peak flows, consistent with the understanding of the catchment’s sensitivity to longer-duration precipitation and changes in the role of snowmelt. Consequently, flood risk mapping shows a small increase in properties in the Thames catchment potentially at risk of riverine flooding, with a substantial range of uncertainty, demonstrating the importance of explicit modelling of impacts and relatively subtle changes in weather-related risks when quantifying present-day effects of human influence on climate