The cell is the basic unit of all known living organisms, and humans consist of many different types of cells, the majority of which are highly specialised. In order to function properly, cells need to communicate with their environment and with neighbouring cells. This requires the transmission of information across the cell membrane, which separates the cellular content from the extracellular environment. One major mechanism of communication is the movement across cell membranes of ions - mainly sodium, potassium, calcium and chloride - through channel-forming proteins that are located within the membrane, so-called ion channels. Many human diseases result from abnormalities in the function of ion channels, and many successful therapeutic drugs work by activating or blocking ion channels. Our research focuses on ion channels called TRPC4 and TRPC5 channels, which are increasingly recognised as potential drug targets in a variety of diseases - including cancer, heart failure, cardiovascular and metabolic disease, epilepsy and anxiety disorders - but for which the development of activators and blockers as drugs has proven difficult. For example, we previously discovered that Englerin A, a natural product isolated from an African tree used in traditional medicine, selectively kills renal cancer cells by the potent activation of TRPC4 channels. Englerin A is also a very potent activator of TRPC5 channels. However, Englerin A is too unstable and too toxic to be used as an anti-cancer drug. In this project, we will study how Englerin A interacts with TRPC4 and TRPC5 channels . We will use a combination of experimental approaches, building on the specific expertise of the different team members. For example, we will use analogues of Englerin A that can chemically react with TRPC4/5 channels, and use mass spectrometry to identify where in the channels the reactions take place. In addition, we will use state-of-the-art electron microscopes - part of a recent £17m investment by the University of Leeds and the Wellcome Trust - to determine the three-dimensional structures of TRPC4/5 channels and their complexes with Englerin A. These results will reveal how Englerin A works on the molecular level, and how the activity of TRPC4/5 channels can be regulated by small molecules. This will enable future development of drugs that targets specific TRPC4 or TRPC5 channels, which may lead to the development of the first drugs that target these channels. We will ensure the future use of our results in the drug discovery process through our ongoing collaboration with the Lead Discovery Center of the Max Planck Society, with the aim to develop drug-like molecules for clinical trials. In addition, we will publish our results in open access publications, and make our data and materials freely available through public repositories.

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Bacteria are much smaller and simpler organisms than us; they only have one cell. Yet we still do not understand how they function. In particular it is frustrating that we do not understand how they are able to protect themselves from antibiotics - and indeed this is one of the main impediments to the rational development of effective novel antibiotics. Gram-negative bacteria are surrounded by a cell envelope which protects the cell and acts as a filter for the movement of molecules into and out of the cell; waste molecules are allowed to exit, essential nutrients are allowed to enter, whereas harmful molecules are by and large kept out. Currently we do not understand how this is achieved at the level of individual molecules let alone atoms. The MOLSimage programme aims to develop a detailed understanding of the cell envelope that protects bacteria- this is of interest from a fundamental biophysics perspective, but also for the future will be important for developing new antibiotics. We will employ computational methods in combination with new advances in imaging technology being pioneered in the UK, to study the cell envelope in as much detail as possible. Rather than use the current approach of studying individual proteins or small groups of proteins, we will study realistically crowded systems to capture all of the relevant details. The combination of computational and experimental will be such that as increasing computing power becomes available, increasingly larger portions of the cell envelope will become tractable. Our methods will take the snapshots in time produced by the imaging methods, interpret and augment them such that additional molecules (that are too small to be picked up the imaging) are added and then the snapshot is subjected to molecular dynamics for time evolution of the systems. The protocols and methods we develop will firmly place the UK in a world-leading position in terms of studying bacterial cell envelopes.

The world's mountains host some of the most complex, dynamic, and diverse ecosystems. But these environments are under severe threats, ranging from local deforestation and soil degradation to global climate change. Global climate models project stronger warming at high elevations, with potentially disastrous consequences for its ecosystems services (ESS). For instance, melting glaciers alone will affect the water supply of millions people, while soil degradation and erosion put local agricultural practices in danger, but also cause water quality degradation and siltation of downstream reservoirs. At the same time, the complexity of mountains also makes predicting the direction of future changes in ecosystem services extremely difficult. For instance, global climate models do not capture the local weather patterns, and traditional models of the natural and physical processes may not represent the extreme and region specific behaviour. This leads to large uncertainties in future predictions about mountain ESS. Under such conditions, the value of day-to-day information about how local ecosystems behave increases sharply. Continuous monitoring of crucial ecosystem processes becomes paramount. It allows local decision-makers to flexibly change course in response to unexpected behaviour and large uncertainties. However, because of their remote location and difficult access, monitoring ESS in mountain regions tends the lag behind the rest of the world. The same remoteness and lack of access are also responsible for the propensity of mountain regions to host poor and underdeveloped communities compared to the surrounding lowlands. Lastly, mountain regions tend to be more prone to conflict, which further inhibits human development. This project will analyse how monitoring and knowledge generation of ESS in mountain regions can be improved, and used to support a process of adaptive, polycentric governance focused on poverty alleviation. For this, we will blend cutting-edge concepts of adaptive governance with technological breakthroughs. The availability of cheap and robust sensors and communication technologies provides great opportunities for citizen science: bottom-up, user oriented data collection focused on local concerns. We will take citizen science to a next level, by integrating it in a broader framework of participatory data processing, knowledge generation and sharing. We do this by adopting the concept of Environmental Virtual Observatories (EVOs) and leverage it for poverty alleviation. We see the potential of EVOs to be decentralised and open technology platforms for knowledge generation and exchange that enable participation of marginalised and vulnerable communities bypassed by the traditional mechanisms. Therefore, in this project we will analyse how EVOs can be used to generate knowledge and to alleviate poverty in 4 remote and poor mountain regions: the Ethiopian highlands around lake Tana, the Central Tien Shan Mountains of Kyrgyzstan, the Kaligandaki watershed in Northern Nepal, and the Andes of central Peru. In each location, we will collect evidence on the local decision-making processes on ESS and their local socio-economic context. At the same time, we will develop a technology toolset to enable EVO development for each case. Subsequently, the results of both processes will be brought together to implement tailored EVOs to support citizen science and local knowledge generation. We will create novel ways to interact with EVOs beyond the traditional Internet focussing on leaflets in the national language, community radios, and mobile phone applications. We will evaluate how the improved access to local observations fosters cross-scale linkages between the poor and external actors, as well as linkages between communities and marginal groups. Lastly, we will investigate how this can lead to better community awareness of environmental change and identification of pathways for poverty alleviation.

Conjugated organic materials are important because of their unique optical and electronic properties. For example organic semiconductors are finding applications in displays, flexible transistors and photovoltaic materials, while two-photon dyes are used in microfabrication, biological imaging and optical signal processing. This field has advanced tremendously during the past 20 years and provides excellent examples of the translation of fundamental science into practical applications that impact everyday life. However there are many open questions concerning the engineering and control of organic pi-systems. Fundamental studies are required to underpin further long-term technological innovations. In this proposal, we build on a new synthetic route to cyclic conjugated polymers, based on supramolecular organisation of precursor molecules. 'Vernier templating' is a new strategy for creating molecules with dimensions comparable to those of structures made by top-down engineering techniques, such as electron-beam lithography. The chemical synthesis of mesoscopic structures provides benefits through the introduction of functionality with atomic precision. We will exploit this methodology to study a previously unexplored region of structure-space and to generate completely new functional materials. Conjugated macrocycles or 'annulenes' have been a focus of research ever since the classical studies by Sondheimer in the 1960s. Large annulenes exhibit remarkable optoelectronic properties, and this has stimulated a resurgence of activity in the field. Anderson's group has contributed to the area by developing the template-directed synthesis of belt-like nanorings of 6, 8 or 12 porphyrin units, with diameters of 2-5 nm. This project will investigate the chemistry and physics of these nanorings, and extend the synthesis to even larger structures. The porphyrin nanorings targeted here are of great interest in their own right, owing to their similarity to natural light harvesting systems, and because they are expected to support the quantum coherent transport of charge and excitation. They also provide a new model system in which to explore the synthesis of mesoscopic molecules with well defined shapes. The templating procedures pioneered in Oxford are likely to stimulate developments in related fields such as molecular machines and biomimetic chemistry, where the controlled synthesis of large molecules with complex functionality remains a bottleneck for future developments. We focus on alkyne-linked metalloporphyrin oligomers as test systems which allow access to new functional materials. The fascinating interplay between synthesis, structure and function for these materials motivates the collaborative approach proposed here. Understanding the flow of energy and electrons through molecules is fundamental to many areas of science. We will investigating the delocalisation of energy and charge in nano-scale molecular wires with well defined tertiary structures. Conventional ring currents have only been observed in molecules with diameters of less than 2 nm, however semiconductor rings with diameters of about 10 nm exhibit persistent ring currents, in the absence of an applied voltage. These quantum-interference phenomena are analogous to the ring currents of aromatic molecules, except that they vary with the applied magnetic field (i.e. they exhibit Aharonov-Bohm oscillations). We will investigate whether molecular nanorings exhibit behaviour intermediate between those of small aromatic molecules and large quantum rings. Porphyrin nanorings resemble the light harvesting chlorophyll arrays which funnel energy into the reaction centre during photosynthesis. We will explore whether they mimic the excitonic behaviour of natural light harvesting arrays. Ultimately this work may lead to improved materials for solar power generation, or to molecular solenoids and split-ring resonators which function as optical metamaterials.