BBK

The papillomaviruses are an important class of disease causing organism in animals and man. Bovine papillomavirus (BPV-1) is the model of the group and the consequences of disease (interference with suckling, milking and breading), has a significant economic impact worldwide. The highly related human viruses (HPV) cause cancer and therefore also have a negative impact on quality of life. The mechanisms of viral replication are consequently of significant interest as the viral replication proteins are important therapeutic targets. The survival and continuity of an organism, be it a virus or man, requires duplication of its genetic material- its DNA- and this is performed by specialized proteins. The first important step in this process is the recognition of specific 'origins of DNA replication' by proteins that separate, or "melt", the two otherwise paired strands of the DNA ('the DNA double helix'). In higher organisms like man, the timing and physical precision of this 'initiation' event is crucial to avoid the catastrophic consequences that may result from any loss of genetic material (for example, cancer). After the initial melting of the DNA at localized site, complete separation of the two helical DNA strands is performed by 'helicase' proteins. DNA strand separation by initiator and helicase proteins is generally poorly understood in simple organisms like viruses as well as higher species like man. However, the process appears to be highly conserved, suggesting that mechanism may be generally similar in all systems. We propose here to explore and characterize these replication processes in BPV-1. The advantage is that all the viral DNA replication activities are performed by a single protein called E1, thus simplifying the study. We will use powerful microscopes to take snapshots of different steps of the process and biochemical techniques that will help to define mechanisms. These studies will therefore contribute significantly to the understanding of the papillomavirus replication protein that is an important therapeutic target. Modeling these replication events in this simplified viral system will also help us understand the process in man. These studies will therefore assist in disease management and improving human and animal health.

The proposed project aims at analysing the potentials, functions and limits of strategic human rights litigation for the reassertion of refugee rights in the Mediterranean border zone. More specifically, I will analyse legal court cases brought against Italy and the EU in national and international fora regarding the deaths and push-backs of migrants in the Mediterranean Sea. To do so, I will conduct ethnographic fieldwork in strategic human rights organisations, conduct interviews and review and build on the available academic literature. My research questions are:(1) What role does strategic litigation play in the Mediterranean border landscape? How does it reconfigure the borders of Europe?(2) What is the strategic significance of litigation in the Mediterranean border zone? In how far does strategic litigation allow refugees and migrants to effectively access their rights?(3) How does strategic litigation intervene amongst the variety of tactics and strategies used to challenge the situation of rightlessness that refugees and migrants are faced with? What does the resort to legal means tell us about the ways in which the current border regime can be contested? I am already in contact with key academics and practitioners working on strategic litigation and will continue to foster our partnership to answer my research questions. Accordingly, my research project is congruent with ESRC's aim of working innovatively across disciplinary, institutional and professional boundaries. The project is also relevant to ESRC remit because it promises to have a strong academic and societal impact, for example on the policies of countries of destination of migrants and refugees. It is aimed at assessing the effectiveness of litigation, which is one of the many tools to seek democratic accountability and thereby affects our perception of the rule of law and the possibility of achieving justice.

Risk is a very important concept in many areas of every day life. Risk is the potential of gaining or losing something of value. The values include physical health, social status, emotional well-being or financial wealth, etc. Values can be gained or lost when taking risk resulting from a given action or inaction, foreseen or unforeseen. In real-life, many decisions are made to averse risks. For instance, most factories would choose to produce at a lower speed to avoid high risk of flawed products. Likewise, many people would not choose high-stake asset allocation portfolios with the possibility of high wins and losses. There are, however, other cases where risk-seeking actions are preferred, such as gambling. It is then of utmost importance to take risks into consideration when modelling a system. Markov decision processes (MDPs) is a general mathematical framework to model a system. They are used in a wide area of disciplines, such as robotics, automated control, economics, and manufacturing. In many applications modelled by MDPs, it is crucial to incorporate some measure of risk to rule out, for instance, policies that achieve a high expected reward at the cost of risky and error-prone actions. As a result, risk-sensitive optimality criteria for MDPs were put forward. In the last decade, the notion of risk measures has become very popular. Intuitively a risk measure is a function that maps a cost or reward to a real value, and the aim is to minimise the risk measure. Despite the existing work on risk measures in MDPs, there are still many questions to be answered in this area: what is the computational complexity, how to develop efficient algorithms, or how to provide effective tool support, just to name a few. The proposed research is to address those questions in depth. The results will shed some lights on whether the risk measure minimisation problem can be performed efficiently at all. If so, how to perform efficiently? If not, is there an efficient algorithm to compute a close enough solution? On top of the algorithmic results, how to develop a ready-to-use tool to calculate the minimal risks? The ultimate goal is to provide a strategy to guide the decision making so that risks are minimised. This can, for instance, help people distribute their asset portfolio, or give advice on the manufacturing processing, or control the robot to deliver a safe and cost-economic path, etc.

Our perception of the external visual world and the ways in which we interact with this world are strongly affected by our current expectations, intentions, and our previous experience. Even though we may subjectively feel that our conscious experiences and our actions are primarily determined by the outside world, it is our active mind that shapes what we perceive and how we react to the external world at any given moment. What we become aware of is determined by what we attend to, and what we attend to is determined by "images in the mind" (attentional templates) that guide our attention in line with our goals and preferences. The essential role of the active guiding mind in the control of attention was already highlighted by William James in 1890, but we still know surprisingly little about the nature of attentional templates, and about how these templates determine which object(s) are attended at any time. In the research proposed here, we will apply new experimental procedures and new methodological techniques (including temporally precise measures of electrical brain activity obtained while observers are engaged in attentional selection tasks) to answer some of the fundamental questions that have been debated by experimental psychologists for more than a century. We will investigate how many things we can attend to at any time, and expect to find that the answer suggested by William James ("not easily more than one") may be correct. We will study the adverse consequences of having to simultaneously attend to multiple objects in perception, visual working memory, and action. Are there systematic differences between individuals in their ability to attend to more than one thing at a time? Is this ability age-dependent and can it be improved by training? We will also investigate how the "image in the mind" is organised: Do attentional templates represent integral visual objects, or do they include lists of the visual features that define a current goal object? An answer to this question will have important consequences for current theoretical models of how attention operates. Finally, and very importantly, we will develop new methods to obtain precise measures of the speed of voluntary visual attention shifts: If attention is engaged at a particular location, how fast can it be moved to a new potentially relevant object? And how fast can we change the "image in the mind" if we want to guide our attention to a different object? Our initial results suggest that the top-down guidance of attention can be much faster and is more flexible than is usually believed, and we will now find out whether and under which circumstances this is the case. The question how "images in the mind" control conscious experience and voluntary action is central to theories of selective attention. Finding new answers to this question will have important general theoretical and conceptual implications for attention research. But our research is also important from an applied perspective. A defining feature of life in our technologically advanced society is the attentional competition between multiple sources of information, which result in permanent demands on attentional object selection and choice. New insights into how attentional templates guide what individuals perceive and how they choose to act therefore has obvious practical implications for areas as diverse as education, workplace design, and economic decision making.

Cataract is an opacity of the eye lens caused by changes to long-lived proteins, known as crystallins. One protein called alpha-crystallin, surveys other proteins inside the lens checking for faults. As we get old, these tend to build up. Our aim is to use X-ray crystallography to image the molecular structure of this protein to find out how it works. Proteins are linear chains that fold into complex patterns that unravel with time. Unfolded crystallins left unattended will clog together and scatter light. For most of our life alpha-crystallin recognizes when things are wrong, soaking up damaged proteins. But with age so much protein has changed and there is no fresh alpha-crystallin left. We aim to work out the sorts of changes that cause crystallins to unfold, and the faults alpha-crystallin recognizes. Changes to crystallin genes cause childhood cataracts. We aim to assess the impact these changes make to lens proteins by laboratory experiments and by simulating crystallin unfolding using computers. We want to know what the protein looks like when things start to go wrong, in case it can be reversed. This will contribute towards the discovery of drugs that delay cataract for a few years, reducing the need for surgery.