EPSRC : Andrew Bage : EPSRC/3202/R83279 The pharmaceutical and agrochemical industries are dependent upon the construction of novel molecular structures to target new medicines and agrochemicals. One of the most generally applied and used methods to do this uses arylboronic esters building blocks. Therefore an extensive library of arylboronic esters is needed and the easy ability to continually increase this library is essential. The greater the library, the greater the potential for novel chemical structures. Arylboronic esters are currently prepared by a two-step process which is inherently wasteful and practically challenging. The direct production of arylboronic esters by C-H borylation is far more economic and has the potential to become a staple reaction, particularly for the medicinal chemistry and agrochemical industries. Currently, rare, toxic metals, typically iridium and rhodium, are used as catalysts for the C-H borylation reaction, but the reactions suffer from limited selectivity. This project will introduce broad-scope and selective boron-based catalysts for C-H borylation to give arylboronic esters. A boron-based catalyst would offer orthogonal reactivity and remove the need for exhaustive catalyst removal, as boron is far less toxic than the heavy metals currently used. The Fontaine group is the world leader in boron-based C-H borylation reactions. They have developed a series of stoichiometric and substoichiometric boron species that are capable of activating aryl C-H bonds to further reaction. The Thomas group has shown stoichiometric boron species can be transformed into catalysts by utilising the 'boron-boron exchange' mechanism. This mechanism shows impressive versatility and is vital to catalyst regeneration. Boron-boron exchange has been used to prepare alkyl- and alkenylboronic ester products and it will be applied to arene C-H borylation in this project. Initially, stoichiometric C-H borylation will be used to probe the efficacy of the boron-boron exchange mechanism for C-H borylation. This will include isolating reaction intermediates and directly observing exchange and catalyst regeneration. Subsequently, we will develop catalytic reactions using the fundamental knowledge gained. Optimisation will focus on functional group tolerance and the targeting of arylboronic esters of significant interest to the pharmaceutical and agrochemical industries. Ultimately, this project will showcase boron-boron exchange as a versatile tool for developing industrially-relevant building blocks and give a system that will rival current industrial methods for C-H borylation.

On a local and international scale, urban heritage is a powerful vector for development and the enhancement of identities, as well as a lever for the tourist economy and many aspects of regional planning. The enhancement of urban heritage is studied mainly from the point of view of the public sector. The present project aims to shed light on the role played by property developers in the process of urban heritage development. To do so, it looks at the multiple strategies, particularly land strategies, that are deployed by property developers and seeks to situate the place that urban heritage occupies within them. The project pays particular attention to the relationship between heritage and sustainable development within the strategies and discourses of property developers. It reinterprets the concept of the neoliberal city by showing that 1) it can include a set of complex, varied and innovative arrangements within a very circumscribed territory that challenge its domination by a homogeneous ethos; 2) although conflicts can arise around the values accorded to tangible and intangible heritage, arrangements can be found around heritage that reconcile uses, exchange values and sustainability. The project is based on two case studies that have been the subject of heritage policies supported by the inscription on the UNESCO list of World Heritage sites, Quebec City and Bordeaux, which are also twinned cities. It is particularly interested in the strategies of promoters who give a very important place to urban heritage in their "city making" (GM Développement and Norplex in Quebec and ID&AL Groupe and Pierranova in Bordeaux). The interdisciplinary consortium, specialised in urban and heritage issues, will use mainly qualitative methodological tools.

Phages with tails (Caudovirales) belong to three families, among which Siphoviridae possess a non contractile tail terminated by a tail tip or a baseplate serving for phage adsorption on its host. While the mechanism of bacterial infection by the two other Caudovirales families has been well documented, much less is known concerning infection of gram+ by Siphoviridae. Our group aims at deciphering the mechanisms underlying infection of Lactococcus lactis by siphophages. L. lactis, a Gram+ bacterium, and its bacteriophages (siphoviridae, dsDNA), are a topic of economical and scientific importance. Lactococcus lactis infection by virulent phages is an economical problem impairing any industrial milk fermentation for cheese production, because virulent phages are ubiquitous within their process environments as well as within pasteurized milk. Besides, several hundreds of L. lactis phages have been isolated worldwide, each phage infecting specifically one or a few L. lactis strains. In a previous project, we have determined the crystal structures of the receptor binding proteins (RBPs) from lactococcal phages, p2 and TP901-1, because the first step of infection involves the specific interaction of the phage RBP with the saccharidic host receptor evenly distributed at the surface of cell walls. The RBPs are attached to a phage organelle, the baseplate, which orientates it properly for receptor recognition. We have determined the structures of the phages p2 and TP901-1 baseplates by EM and X-ray diffraction. These two organelles (1.1 and 1.9 MDa) harbour 18 and 54 sugar binding sites, respectively. We have shown that p2 baseplate changes conformation in the presence of Ca++, a cation strictly necessary for infection. The 3D knowledge of the components of the baseplates revealed that many of them possess conserved structures. In particular we had shown that a common protein forms a baseplate hub of most gram+ infecting siphophages. Furthermore, some of these structural features are shared with other phages (Myoviridae) or even with the bacterial type VI secretion system. The present projects aims at keeping the momentum acquired. We have enormously progressed in understanding the mechanism of host recognition, still, we do not understand how the recognition event generates a signal, which, transmitted along the tail, triggers the capsid’s portal protein opening and DNA release. A first possible mechanism involves conformational changes of the major tail proteins (MTPs) induced by the baseplate activation. It might then propagate along the tail up to the terminator, and finally trigger the portal opening. A second hypothesis is based on a bell-ringing mechanism. The central component of the tail, the tail measure protein (TMP), might be pulled by the baseplate movement, which in turn would act on the portal protein. The portal trigger mechanism is likely general among siphophages and extends thus the generality of our project. Deciphering the trigger mechanism requires approaches in several directions. We will first examine by electron microscopy (EM) the effect of the receptors on the complete phage, ie, the conformational changes of the baseplate and eventually of the tail before and after DNA release. A second approach will involve the production (in E.coli or L.lactis) of complexes larger than the baseplates, incorporating all the components of the baseplate and tail, as well as receptor saccharides. Indeed, the tail size will be decreased to a few hexameric rings of the MTPs by reducing the size of the TMP. These constructions will be examined jointly by cryoEM and X-ray diffraction, in order to determine which of the two above-described mechanism is most likely. The virologists will provide the phages and perform functional infection assays of putatively important mutants identified by structural studies. Our ultimate goal is to assemble sufficient data to present a realistic “film” of viral infection, up to DNA ejection.