Film support and the challenge of ‘sustainability’: on wing design, wax and feathers, and bolts from the blue

In recognition of the importance of film in generating both economic and cultural value, the UK Labour government set up a new agency – the United Kingdom Film Council (UKFC) – in 2000 with a remit to build a sustainable film industry. But, reflecting a plethora of differing expectations in relation to the purposes behind public support for film, the UKFC's agenda shifted and broadened over the organisation's lifetime (2000–11). Apparently unconvinced by the UKFC's achievements, the Coalition government which came to power in May 2010 announced the Council's abolition and reassigned its responsibilities as part of a general cost-cutting strategy. Based on original empirical research, this article examines how the UKFC's sense of strategic direction was determined, how and why the balance of objectives it pursued changed over time and what these shifts tell us about the nature of film policy and the challenges facing bodies that are charged with enacting it in the twenty-first century

Foxn1 Regulates Lineage Progression in Cortical and Medullary Thymic Epithelial Cells But Is Dispensable for Medullary Sublineage Divergence

The forkhead transcription factor Foxn1 is indispensable for thymus development, but the mechanisms by which it mediates thymic epithelial cell (TEC) development are poorly understood. To examine the cellular and molecular basis of Foxn1 function, we generated a novel and revertible hypomorphic allele of Foxn1. By varying levels of its expression, we identified a number of features of the Foxn1 system. Here we show that Foxn1 is a powerful regulator of TEC differentiation that is required at multiple intermediate stages of TE lineage development in the fetal and adult thymus. We find no evidence for a role for Foxn1 in TEC fate-choice. Rather, we show it is required for stable entry into both the cortical and medullary TEC differentiation programmes and subsequently is needed at increasing dosage for progression through successive differentiation states in both cortical and medullary TEC. We further demonstrate regulation by Foxn1 of a suite of genes with diverse roles in thymus development and/or function, suggesting it acts as a master regulator of the core thymic epithelial programme rather than regulating a particular aspect of TEC biology. Overall, our data establish a genetics-based model of cellular hierarchies in the TE lineage and provide mechanistic insight relating titration of a single transcription factor to control of lineage progression. Our novel revertible hypomorph system may be similarly applied to analyzing other regulators of development

Natural Compatibilism, Indeterminism, and Intrusive Metaphysics

The claim that common sense regards free will and moral responsibility as compatible with determinism has played a central role in both analytic and experimental philosophy. In this paper, we show that evidence in favor of this “natural compatibilism” is undermined by the role that indeterministic metaphysical views play in how people construe deterministic scenarios. To demonstrate this, we re-examine two classic studies that have been used to support natural compatibilism. We find that although people give apparently compatibilist responses, this is largely explained by the fact that people import an indeterministic metaphysics into deterministic scenarios when making judgments about freedom and responsibility. We conclude that judgments based on these scenarios are not reliable evidence for natural compatibilism

Evolutionary Games with Affine Fitness Functions: Applications to Cancer

We analyze the dynamics of evolutionary games in which fitness is defined as an affine function of the expected payoff and a constant contribution. The resulting inhomogeneous replicator equation has an homogeneous equivalent with modified payoffs. The affine terms also influence the stochastic dynamics of a two-strategy Moran model of a finite population. We then apply the affine fitness function in a model for tumor-normal cell interactions to determine which are the most successful tumor strategies. In order to analyze the dynamics of concurrent strategies within a tumor population, we extend the model to a three-strategy game involving distinct tumor cell types as well as normal cells. In this model, interaction with normal cells, in combination with an increased constant fitness, is the most effective way of establishing a population of tumor cells in normal tissue.Comment: The final publication is available at http://www.springerlink.com, http://dx.doi.org/10.1007/s13235-011-0029-

Quantitative Interpretation of a Genetic Model of Carcinogenesis Using Computer Simulations

The genetic model of tumorigenesis by Vogelstein et al. (V theory) and the molecular definition of cancer hallmarks by Hanahan and Weinberg (W theory) represent two of the most comprehensive and systemic understandings of cancer. Here, we develop a mathematical model that quantitatively interprets these seminal cancer theories, starting from a set of equations describing the short life cycle of an individual cell in uterine epithelium during tissue regeneration. The process of malignant transformation of an individual cell is followed and the tissue (or tumor) is described as a composite of individual cells in order to quantitatively account for intra-tumor heterogeneity. Our model describes normal tissue regeneration, malignant transformation, cancer incidence including dormant/transient tumors, and tumor evolution. Further, a novel mechanism for the initiation of metastasis resulting from substantial cell death is proposed. Finally, model simulations suggest two different mechanisms of metastatic inefficiency for aggressive and less aggressive cancer cells. Our work suggests that cellular de-differentiation is one major oncogenic pathway, a hypothesis based on a numerical description of a cell's differentiation status that can effectively and mathematically interpret some major concepts in V/W theories such as progressive transformation of normal cells, tumor evolution, and cancer hallmarks. Our model is a mathematical interpretation of cancer phenotypes that complements the well developed V/W theories based upon description of causal biological and molecular events. It is possible that further developments incorporating patient- and tissue-specific variables may build an even more comprehensive model to explain clinical observations and provide some novel insights for understanding cancer

Framing the Real: Lefèbvre and NeoRealist Cinematic Space as Practice

In 1945 Roberto Rossellini's Neo-realist Rome, Open City set in motion an approach to cinema and its representation of real life – and by extension real spaces – that was to have international significance in film theory and practice. However, the re-use of the real spaces of the city, and elsewhere, as film sets in Neo-realist film offered (and offers) more than an influential aesthetic and set of cinematic theories. Through Neo-realism, it can be argued that we gain access to a cinematic relational and multidimensional space that is not made from built sets, but by filming the built environment. On the one hand, this space allows us to "notice" the contradictions around us in our cities and, by extension, the societies that have produced those cities, while on the other, allows us to see the spatial practices operative in the production and maintenance of those contradictions. In setting out a template for understanding the spatial practices of Neo-realism through the work of Henri Lefèbvre, this paper opens its films, and those produced today in its wake, to a spatio-political reading of contemporary relevance. We will suggest that the rupturing of divisions between real spaces and the spaces of film locations, as well the blurring of the difference between real life and performed actions for the camera that underlies much of the central importance of Neo-realism, echoes the arguments of Lefèbvre with regard the social production of space. In doing so, we will suggest that film potentially had, and still has, a vital role to play in a critique of contemporary capitalist spatial practices

A Tale of Many Cities: Universal Patterns in Human Urban Mobility

The advent of geographic online social networks such as Foursquare, where users voluntarily signal their current location, opens the door to powerful studies on human movement. In particular the fine granularity of the location data, with GPS accuracy down to 10 meters, and the worldwide scale of Foursquare adoption are unprecedented. In this paper we study urban mobility patterns of people in several metropolitan cities around the globe by analyzing a large set of Foursquare users. Surprisingly, while there are variations in human movement in different cities, our analysis shows that those are predominantly due to different distributions of places across different urban environments. Moreover, a universal law for human mobility is identified, which isolates as a key component the rank-distance, factoring in the number of places between origin and destination, rather than pure physical distance, as considered in some previous works. Building on our findings, we also show how a rank-based movement model accurately captures real human movements in different cities

Ordering of mutations in preinvasive disease stages of esophageal carcinogenesis.

Cancer genome sequencing studies have identified numerous driver genes, but the relative timing of mutations in carcinogenesis remains unclear. The gradual progression from premalignant Barrett's esophagus to esophageal adenocarcinoma (EAC) provides an ideal model to study the ordering of somatic mutations. We identified recurrently mutated genes and assessed clonal structure using whole-genome sequencing and amplicon resequencing of 112 EACs. We next screened a cohort of 109 biopsies from 2 key transition points in the development of malignancy: benign metaplastic never-dysplastic Barrett's esophagus (NDBE; n=66) and high-grade dysplasia (HGD; n=43). Unexpectedly, the majority of recurrently mutated genes in EAC were also mutated in NDBE. Only TP53 and SMAD4 mutations occurred in a stage-specific manner, confined to HGD and EAC, respectively. Finally, we applied this knowledge to identify high-risk Barrett's esophagus in a new non-endoscopic test. In conclusion, mutations in EAC driver genes generally occur exceptionally early in disease development with profound implications for diagnostic and therapeutic strategies