Every cell within our body carries the same genetic information (DNA), yet following iterative developmental transitions hundreds of morphologically and functionally distinct cell types are being generated. At the foundation of this fascinating cellular diversification lies a milieu of finely orchestrated and sophisticated regulatory programmes, which act to turn on or off thousands of genes (~20,000 in humans) with minute spatial and temporal precision. Errors in these programmes can give rise to developmental defects and many human diseases including cancer. One such essential regulatory layer is provided by microRNAs (miRNAs). miRNAs are fascinating RNA molecules comprised of only 21 to 23 letters of the genetic alphabet, and are never translated into a polypeptide chain (protein). Strikingly, these tiny pieces of RNA appear to act as molecular rheostats of gene expression programs (protein production) in almost every living organism, by binding to numerous messenger RNAs (mRNAs) via defined "miRNA response elements" (MREs). Therefore, central to understanding cellular pathways regulated by miRNAs, is identification of their direct functional targets (MREs) in vivo. Paradoxically, this essential facet of miRNA biology has met with relatively limited success to date. Due to the complexity of the cellular environment, identifying all functional targets of a miRNA in the context of a living cell requires a systems biology approach, which hitherto had been technically unfeasible. Here, we propose to develop an innovative high-throughput discovery pipeline, which will enable for the first time a systems-level functional characterization of any primary miRNA target network. At the core of this revolutionary approach lies the development and assembly of two cutting edge technology platforms: i) a multiplex genome engineering-based strategy for assessing MRE activity; ii) a platform for parallel interrogation of miRNA target site accessibility. Integration of these tools in a combinatorial mode will engender unprecedented insight into the principles and rules governing miRNA target selection in vivo, thus addressing this fundamental, yet unmet, dimension in miRNA biology. Therefore, we anticipate that this endeavour will have a major impact on the research community, empowering scientists with the ability to understand, predict, and assess the impact of miRNAs in the context of a living cell. Considering the interdisciplinary nature underlying this research, the proposal brings together four leading international research centres: Weatherall Institute of Molecular Medicine Oxford, Genome Engineering Centre Oxford, Oxford Genomics Centre (WTCHG), and the EMBL European Bioinformatics Institute (EMBL-EBI) Cambridge.

It has long been hypothesised that the abnormal and heterogeneous architecture of tumour vascular networks promotes irregular spatio-temporal variations in blood flow rates, haematocrit distribution, and consequent oxygen delivery. These irregularities can cause the formation of cyclic hypoxic areas - regions experiencing transient periods of oxygen deprivation and reoxygenation. Exposure to such fluctuating oxygen levels is assumed to select and promote metastatic spread and resistance to radio- and chemo-therapy. Consequently, understanding the microstructural and fluid-dynamic mechanisms that promote macroscopic oxygenation oscillations and how they may be clinically altered is of great importance. The goal of this project is to develop a multiscale mathematical framework to model blood flow and oxygen transport within vascular tumours, in order to shed light on the links between microscopic haemodynamic mechanisms and the emergence of cycling hypoxia at the macroscale. The methodology will be based on multiple-scale homogenisation - a formal mathematical approach used to derive systems of continuum equations, by upscaling descriptions of transport phenomena from the single capillary scale to the macroscopic scale of the tumour. Using this method, I will establish how microstructural vascular heterogeneities, together with flow-nonlinearities induced by haematocrit-dependent blood viscosity and biased haematocrit partitioning at vessel branch-points, can lead to macroscopic flow-oscillations and consequent unsteady tissue oxygenation. The mathematical framework thus developed could be used, in the longer term, to identify tumour structures that will benefit from transient vascular normalisation treatments, to predict the consequent effect of such protocols on diminishing hypoxia, and thereby improve and personalise tumour responses to existing treatments.

My research concerns the social dynamics of openness in artificial intelligence (AI) research and development, with a particular focus on the social and technical networks of open source software sharing and development. My research will blend social theory with a suite of data science methods to interrogate uneven participation and influence in this community of practice, operationalised through three separate but interrelated studies on this subject matter. The first study will examine the social and technical network structure of open source AI software development on the software hosting platform GitHub, due to its popularity and data availability via its Public API. Upon the collection and preparation of data recording ties between developers and software projects, I will use network science techniques to examine the network structure of collaboration in AI software projects as well as who and whose software have emerged as central authorities in this community. The study will contribute to academic scholarship of social networks in science and technology fields as well as practical outputs oriented at raising awareness of uneven participation and influence in the field of AI. The second study will examine geographic contours and concentrations of open source AI software development and the factors that can explain global disparities. Similarly, I will programmatically collect geo-coded data on software development activities and enumerate these activities on a country-basis. I will use cartographic analysis to map global activity and use multivariate regression analysis to analyse what factors can explain disparities between countries. This analysis will inform policy recommendations targeted at national governments and international organisations on how to broaden global participation in the AI community. The third study will zoom into a handful of practitioners who in semi-structured interviews will be asked whose values and interests do they perceive to influence norms, dependencies, and possible futures in the open source AI software community. Using purposive sampling methods, I will conduct interviews with users identified in the first study. This study will contribute to academic theory on the imaginaries of members of this scientific community of practice. Overall, this project will contribute to work in the academy on inequality in software development as well as inform policymaking aimed at widening participation in this increasingly pivotal field.

PROJECT ABSTRACT: Human immune T-cells are responsible for detecting and destroying infected or compromised cells. This is important for controlling pathogens and cancer. T-cells achieve this by recognising molecular markers on the surface of the target cell through their T-cell receptor (TCR). T-cells also display a variety of Co-signalling receptors that respond to other molecular markers which communicate information on the progression of infection or status of the target cell and its environment. T-cells therefore face the challenge of integrating all of this information to control their response. Failure to effectively regulate T-cell responses are associated with autoimmunity, the destruction of healthy tissue. Cancer cells can also hijack this co- signalling receptor system to evade T-cells and avoid detection/termination. This project aims to use mathematical modelling and machine learning, trained on a large database of T-cell co-signalling receptors, to sample the space of possible signalling networks that can explain how information is relayed and integrated in T-cells. This will allow us to better understand how T-cells appropriately recognize and neutralize compromised targets as well as propose novel synthetic biological circuits to further improve T-cell function in the context of fighting cancer and avoiding autoimmunity. BBSRC PRIORITY AREAS ADDRESSED: Data-driven biology, Synthetic Biology, Systems Approaches to the Biosciences, Technology Development for the Biosciences

The current political dynamics in Egypt are of huge importance to the stability of the country and the Middle East as a whole. Egypt is not just the most populous and culturally the most influential Arab country, whose success as a democracy (and its mode of transition or failure) would have powerful diffusion effects across the region. It is also a cornerstone for stability in the region, having been the first Arab country to sign a peace treaty with Israel. The removal of President Morsi by the Egyptian Army following mass public protests against his rule raises profound questions about the democratic commitments of Egyptian citizens, the future of democracy in Egypt, and the future of 'electoral Islamism', both in Egypt and beyond. There is an urgent need to collect data on Egyptian public opinion at this crucial point in the country's political transition in order to address these questions. Immediately following the parliamentary elections of 2011, a privately funded survey of citizens conducted by the applicants produced three results of great relevance to the present political situation. First, Egyptian public opinion appeared overwhelmingly supportive of democracy as the best way of running the country. Second, differences between supporters of different parties were minimal. A third feature of public opinion at that time, however, illustrated clearly the nature of the country's current democratic cross-roads. Overall, we found very strong levels of support for a 'guardian army', including among a majority of Muslim Brotherhood supporters. Clearly - and this is the nub of the set of issues we propose to investigate - Egyptian public opinion and party representation cannot now hold on the lines of 2011. But, we ask, in what directions are they breaking? From one angle, this may be the moment at which many Egyptians give up a belief in the very democratic principles they called for during the 2011 revolution (that power is transferred through elections, that the military keeps out of politics, that respect for human rights is universal even for those whom some might see as Islamist extremists). From a different angle, the several millions who took to the streets to call for Morsi to resign seemed to be applying, in effect, support for democracy in a format not restricted by the formalities of calling for elections, running a campaign, casting votes and announcing results. The answers are crucial to the democratic future and governability of the country and for the future of 'electoral Islamism'. Consequently, we will conduct two further mass surveys of the Egyptian public - one to be conducted immediately funding and is assured and fieldwork possible, a second to be conducted when elections take place - to investigate how attitudes have changed since the period when Islamists won legislative and presidential elections. Given the broad political and economic importance of the knowledge that our project will produce for a range of user communities - governments, businesses, NGOs, and opinion leaders in the UK and internationally - we will engage in the widest possible dissemination and outreach activities and produce a unique and publicly accessible data set that may be the basis and anchor for further survey research in Egypt.