At present, 40% of all leading compounds that emerge from drug discovery are not developed further due to their poor solubility. Currently, drug molecules are almost exclusively made into a medicine using a crystalline drug which has an inherent solubility disadvantage due to the lattice energy associated with its crystalline state that needs to be overcome before dissolution occurs. The amorphous state, where the molecules are completely disordered and hence the cohesive energy is smaller, is a potential alternative state for drug-molecule formulations. Given that the amorphous state is higher in energy, such drug formulations are currently perceived to be high risk, as it is not possible, using the existing technology and understanding, to predict their stability against recrystallisation reliably. In addition, there is still no comprehensive understanding of the physics of the amorphous state in general and the factors governing devitrification (the crystallisation process from the amorphous phase) even though this area of research has been the focus of very intense activities over the past decades. Unforeseen stability issues due to recrystallisation could lead to enormous costs for pharmaceutical companies if such formulations fail during the later stage clinical trials or, even more catastrophically, once the product is on the market. However, the improvement of solubility in the amorphous state would be sufficient to permit greater than 50% of poorly soluble leading compounds to be selected as candidates for the drug-development pipeline. This would permit an extensive range of hitherto untested chemistries to move through to the clinic to address unmet therapeutic needs for patient benefit. Here, we aim to develop a better understanding of structural changes occurring in organic amorphous formulations of drugs, with the ultimate goal of improving their efficacy and stability. This proposal is developed around the ability to quantify directly terahertz and/or picosecond-nanosecond inter-molecular dynamics that govern the crystallisation in organic amorphous systems. The majority of experimental evidence will be gathered by means of terahertz time-domain spectroscopy (THz-TDS) and low-frequency Raman spectroscopy but will be complemented by theoretical and simulational studies, and other experimental techniques as necessary. There are two ultimate goals of the proposed work: 1) To develop an analytical method that can be used to quantify the likelihood of structural changes, ultimately culminating in crystallisation, occurring in amorphous materials over extended periods. Furthermore, to allow a systematic optimisation of amorphous drug formulations and their storage conditions with respect to their stability against structural changes. 2) To provide high-quality experimental data to stimulate and support the development of theory aimed at better understanding the fundamental physics of non-equilibrium organic solids. If successful, the terahertz or Raman methods could be implemented for drug-development activities almost immediately, as such turn-key equipment is now commercially available and, once we are able to develop the detailed understanding as outlined in this proposal, they can be operated and the data interpreted by technicians, much like any other analytical technique today. The lab-based measurements proposed here could further remove the requirement for costly and time-consuming measurements at central facilities, such as neutron sources, for similar analysis, and thus free up this critical resource for other research activities.

This Network aims to bring together an international group of scholars from different disciplines (including architectural history, history, literature and music) with an interest in the cultures of Enlightenment, reform and radicalism to discuss the complex of ways in which the practice, theory and experience of architecture contributed to debates about modernity and urban experience in the decades around 1800. It will do so through lens of the life of Thomas Rickman (1776-1841), which provides a springboard for discussing many of the issues involved. His internationally influential work, 'An Attempt to Discriminate the Styles of Architecture' (Liverpool, 1817) was the first architectural 'best seller', through which the educated public were taught how to identify and discuss architectural styles. Through studying and writing about architecture, Rickman transformed his identity from depressed bankrupt exile to successful professional architect. Rickman was closely associated with reformist circles, his architectural research was informed by methods of classification learned from the natural sciences and he was a pioneer of new methods of construction, but as a successful practitioner he worked for a wide range of clients, from wealthy industrialists, to Anglican parishes, municipal corporations and Cambridge colleges. His career - and the associated buildings and archive - provides a connecting thread across this project, a springing point for addressing broader research questions and engaging the general public through a touring exhibition, website and associated workshops and walking tours devoted to his life and work. Many of today's debates about the contribution of buildings, both new and old, to societal wellbeing have their counterparts in eighteenth- and early nineteenth-century discourse and juxtaposing the two will contribute a historical dimension to discussion of modern planning and heritage policies. Through networking symposia in Liverpool and London, and research workshops with site visits to buildings in Liverpool, Bristol and Birmingham, the Network will address how, in addition to its existing role as the most prestigious public site of display, architecture became a site of social experiment, embodying decisive shifts in medical, penal and educational theory, to be tested through the impact of new building forms. These debates intertwined buildings and books in a virtual sphere but the public sphere also had a spatial dimension: the new libraries, news rooms and lecture theatres in which such debates were encountered and performed and the transformation of towns through public and private investment (actual and anticipated) through which modernity was imagined and experienced. These involved changing patterns of patronage, funding and building, contributing to the professionalisation of the architect and the emergence of general contracting. The Network aims to frame public discourse about architecture in relation to the transformation of the public sphere, both through changes in print culture and contemporary economic and social changes wrought by war, capitalisation, industrialisation and urbanisation. Through print and travel, this discourse had a global dimension and the Network will develop international connections in order to enable a globally comparative approach. Our objective is to build capacity for ongoing collaboration and future international comparative research.

This project will describe and model long term variations in Earth's magnetic field through the last 500 million years in order to address three major linked controversies regarding the dynamics and evolution of Earth's deep interior: the mobility of large seismically anomalous structures in Earth's lowermost mantle, the age of Earth's inner core, and the nature and causes long-term palaeomagnetic variations. The geomagnetic field, generated in Earth's outer core by the geodynamo process, is a fundamental property of the planet. It shields the atmosphere and life from harmful solar wind radiation and provides a window to the deep interior of the planet which, through palaeomagnetic records, has the unique geophysical capability of being extended back through geological time. Long term variations in Earth's magnetic field (more than 10 million years) are widely thought to reflect the influence of core-mantle evolution on the geodynamo and therefore could provide badly-needed observational constraints on poorly understood deep Earth processes. In particular, they could help resolve a major outstanding controversy concerning the mobility of large structures in the Earth's lower mantle which are argued by some to be static long-lived "thermochemical piles" that dictate the nature of plate tectonics at Earth's surface, but by others to be transient "superplumes" forming in response to surface-dominated processes. They could also help to resolve a major outstanding controversy concerning the age of Earth's inner core; a topic on which members of the assembled research team have recently published conflicting results (differing by approximately 1 billion years) in the leading multidisciplinary journal, Nature. Previous work by our team has focused on palaeomagnetic variations and core-mantle evolution in the Precambrian (older than 540 million years). Now we are in a position to directly address both of the above controversies and the broader question of what, precisely, controls the long term magnetic variations, by focusing on the last 500 million years. In order to do this, we need to answer some fundamental questions: 1. Are palaeomagnetic variations cyclic (with a period of ca. 200 million years) as current records hint? 2. Do all aspects of palaeomagnetic field behaviour (polarity reversal frequency, field strength, and short-term directional variability) vary simultaneously in a predictable way? 3. How would we expect different degrees of mobility of the large lower mantle structures to affect palaeomagnetic behaviour (E.G. In a cyclic way way and/or with all the different aspects of palaeomagnetic field behaviour changing simultaneously?)? 4. How would we expect different inner core ages to manifest themselves in palaeomagnetic behaviour over the last 500 million years? In this project, we will firstly use new measurements and recently published analysis techniques to answer questions 1 and 2 and build a description of palaeomagnetic variations in the last 500 million years that is unprecedented in its quality and usefulness. To answer questions 3 and 4, we will also produce synthetic records of palaeomagnetic variations from numerical models of the geodynamo subject to different core-mantle evolution scenarios. By comparing and contrasting the new observational and synthetic records, we will then be in a position to determine which scenarios are the most realistic (static thermochemical piles or mobile superplumes? Young or old inner core?), to address the outstanding controversies, and to move towards a fully integrated model of core-mantle evolution incorporating the Earth's magnetic field.

Contract farming is growing rapidly in Eastern Africa. This research project will evaluate innovations in contract farming operations designed to increase the benefits wives accrue from the contract. It also evaluates whether this improves the relationship between the household and the firm. It integrates a gender dimension into an otherwise gender-blind area of practice and research. Contract farming is a form of vertical integration within agricultural commodity chains such that a firm has greater control over the production process and final product. Changes in the demand for and supply of agricultural products have increased the popularity of this form of vertical integration in many low-income countries and it is attracting considerable policy and academic attention. While academic work in the 1980s and 1990s offered a mixed assessment of the extent to which contract farming engaged with and benefited smallholders, recent literature offers a much more positive interpretation of smallholder participation. That said, there are still considerable risks for both firms and farms such that contracting operations frequently collapse. For firms, there is a large risk of smallholders side-marketing both inputs and produce. There are also numerous risks for small-scale producers. Two risks are especially important for smallholders: contracting can contribute to a loss of autonomy and control over farm enterprises and a form of dependency on the contracting firm; and, second, the intra-household distribution of labour/income can be altered to the detriment of women's interests. This research project focuses on the last of these risks through evaluating innovations that seek to both increase wives' benefits and to improve the relationships between the firm and the household. This is through adding gender-specific elements to the contract to increase the 'self-enforcement range'. By this we mean that by adding these extra investments within the contract we reduce the likelihood of either party breaking the deal due to a change in market or contextual conditions. The overarching research question is: To what extent and how do gender-specific clauses within contracts improve outcomes for both farms and firms? The subsidiary research questions are: To what extent and how do gender-specific clauses improve the benefits wives accrue from contract farming operations? To what extent and how do such clauses influence farm production? And to what extent and how do such clauses improve the stability and longevity of contract farming relationships? In Malawi, we evaluate the inclusion of a contract for wives to grow and market groundnuts (a conventional crop for women to produce) alongside tobacco to examine effects on yields, prices and, most importantly, the intra-household distribution of labour/income. We do this by combining a randomized design - where members and clubs are randomly assigned the innovation - with a series of qualitative research methods including life history interviews and focus group discussions. The attrition rate (in other words, the number of households dropping from the scheme) will assess whether the farm/firm relationship has changed. In Tanzania, we utilise the same methodology and sequence of research methods but the precise contractual innovation will be determined during the first two months of the project. In the second phase of research, we extend the project to examine gender-specific innovations in palm oil in Ghana and tobacco in Zimbabwe.

The evolution of host plant feeding is critical for understanding insect evolution and in particular the responses of populations to a changing climate. For example, UK butterfly species that have done well in response to a warming climate have typically also expanded or altered their patterns of host plant use, while those that have suffered typically have a narrow host plant range. Here we will explore how butterflies can alter their biochemical responses to allow the exploitation of different host plants. This is a form of phenotypic plasticity, where a single genotype can produce alternative phenotypes under different environmental conditions. Plasticity is an important adaptation that can allow organisms to survive variable and heterogeneous environments and promote longer term divergence and diversification. Plant-feeding insects have to deal with toxic plant chemistry, but in some cases such toxins can also provide an important source of defensive chemicals for the insects. Tropical Heliconius butterflies can either obtain cyanogenic toxins from their Passiflora hosts, or can synthesise their own compounds. We have demonstrated that these butterflies can switch between these two strategies dependent on host chemical composition. When the larval diet lacks toxins that can be sequestered, Heliconius respond by increasing biosynthesis of their own defences. This permits use of a wider range of Passiflora species while maintaining their chemical defences. We can readily distinguish toxins derived from the host plant from those that are made by the butterflies, making this an easily quantifiable form of phenotypic plasticity. However, the genetic and biochemical basis of this plasticity remains unknown, as well as it's ecological importance for niche partitioning. We will first address the ecological context, using targeted metabolomics to track the chemical composition of Heliconius erato across seasons at sites with well characterised host plant use in Brazil and Panama. Next, we will explore the fitness trade-offs between different strategies, addressing the reasons for switching between strategies in a plastic species, Heliconius erato. We will compare growth rate and other life history traits of individuals raised on different diets. We will also compare efficiency of sequestration in a derived specialist species, which obtains its toxins only from a specific host plant. Increased efficiency in the derived lineage is predicted by the 'plasticity first' hypothesis. The other major axis of variation for defensive compounds is their influence on predation, and we will measure toxicity and distastefulness of host-plant derived and synthesised toxins. Third, we will explore how plasticity controlled genetically, testing two alternative hypotheses for the molecular control of plasticity. Using transcriptomics we will estimate changes in gene expression in response to larval diet (presence and absence of host-plant derived toxins), and also test whether plasticity is controlled at the level of protein regulation. Finally, we will explore the evolutionary history of cyanogen biosynthesis across the Heliconiines, using molecular evolutionary approaches across a large data of whole genome sequences. We will study the gain and loss of genes involved in cyanogen uptake and synthesis, comparing generalist with those where cyanogen biosynthesis has been lost. In summary, this integrative study will explore the ecological context, fitness consequences, genetic control and long-term evolutionary trajectory of plasticity in the use of defensive toxins across a diverse group of insects. We will exploit a readily quantifiable and experimentally tractable system in order to understand how butterflies respond metabolically to variation in host plant chemistry. This will have general relevance to understanding how species can respond to a changing climate.