Growth differentiation factor 9: bone morphogenetic protein 15 synergism and the potential involvement of heterodimerization

LetterDavid G. Mottershead, Craig A. Harrison, Thomas D. Mueller, Peter G. Stanton, Robert B. Gilchrist and Kenneth P. McNatt

From brand congruence to the ‘virtuous circle’: branding and the commercialization of public service broadcasting

In debates about the commercialization of public service broadcasting little attention has been paid to the ways in which the public might experience the commercial and public service activities of public service broadcasters and the impact that this may have on attitudes towards public service broadcasting. This is despite the fact that public service broadcasters increasingly depend on public support for their continued survival. Using the case study of the BBC, this article examines the ways in which the corporation has adopted strategic brand management to negotiate the relationship between its commercial and public service activities. Focusing on specific examples of the BBC’s commercial and public services, the article reveals a tension between the corporation’s attempts to ensure that all activities support its public purposes and its need to ensure separation between public and commercial work. Focusing on the consumer’s experience of the BBC brand, the article argues that rather than seeing commercial activity and public service broadcasting as inherently contradictory, we should be looking at the ways in which public service broadcasters can better communicate the relationship between their commercial and public service activities while continuing to argue for the social and cultural value of publicly funded broadcasting

Lack of correlation of stem cell markers in breast cancer stem cells

BACKGROUND: Various markers are used to identify the unique sub-population of breast cancer cells with stem cell properties. Whether these markers are expressed in all breast cancers, identify the same population of cells, or equate to therapeutic response is controversial. METHODS: We investigated the expression of multiple cancer stem cell markers in human breast cancer samples and cell lines in vitro and in vivo, comparing across and within samples and relating expression with growth and therapeutic response to doxorubicin, docetaxol and radiotherapy. RESULTS: CD24, CD44, ALDH and SOX2 expression, the ability to form mammospheres and side-population cells are variably present in human cancers and cell lines. Each marker identifies a unique rather than common population of cancer cells. In vivo, cells expressing these markers are not specifically localized to the presumptive stem cell niche at the tumour/stroma interface. Repeated therapy does not consistently enrich cells expressing these markers, although ER-negative cells accumulate. CONCLUSIONS: Commonly employed methods identify different cancer cell sub-populations with no consistent therapeutic implications, rather than a single population of cells. The relationships of breast cancer stem cells to clinical parameters will require identification of specific markers or panels for the individual cancer

Evaluation of machine-learning methods for ligand-based virtual screening

Machine-learning methods can be used for virtual screening by analysing the structural characteristics of molecules of known (in)activity, and we here discuss the use of kernel discrimination and naive Bayesian classifier (NBC) methods for this purpose. We report a kernel method that allows the processing of molecules represented by binary, integer and real-valued descriptors, and show that it is little different in screening performance from a previously described kernel that had been developed specifically for the analysis of binary fingerprint representations of molecular structure. We then evaluate the performance of an NBC when the training-set contains only a very few active molecules. In such cases, a simpler approach based on group fusion would appear to provide superior screening performance, especially when structurally heterogeneous datasets are to be processed

Assessment of changes in ecosystem service delivery:a historical perspective on catchment landscapes

Although the relationships between habitats and ecosystem services (ESs) have been acknowledged, investigating spatio-temporal change in these has received far less attention. This study assesses the influence of habitat changes on ES delivery across space and time, based on two time points some 60 years apart, 1946 and 2009. A 1946 aerial photo coverage of two catchments in Scotland was used to construct digital photo mosaics which were then visually interpreted and digitised to derive historic habitat maps. Using the Spatial Evidence for Natural Capital Evaluation (SENCE) mapping approach, the derived habitat maps were translated into ES maps. These were then compared with contemporary ES maps of the two catchments, using the same mapping methodology. Increases in provisioning ESs were associated with increases in intensively managed habitats, with reductions in supply capacity of other regulating and supporting ESs associated with loss of semi-natural habitats. ES delivery was affected not only by gross area changes in habitats over time, but also by changes in configuration and spatial distribution of constituent habitats, including fragmentation and connectivity. It is argued that understanding historic changes in ESs adds an important strand in providing baselines to inform options for current and future management of catchments

Meeple Centred Design: A Heuristic Toolkit for Evaluating the Accessibility of Tabletop Games

Evaluation of accessibility within a tabletop context is much more complicated than it is within a video game environment. There is a considerable amount of variation in game systems, game mechanisms, and interaction regimes. Games may be entirely verbal, or completely non-verbal. They might be real-time or turn based, or based on simultaneous actions. They can be competitive or co-operative, or shift from one to the other during a single game session. They might involve visual pattern recognition or force players to memorise game state without visual cues. They may involve touch, or smell. They might involve social deduction or betrayal. They can encompass all sensory faculties, in differing degrees. Almost all games have accessibility considerations that should be taken into account, but there is currently no comprehensive tool by which this can be done that encompasses the rich variety of tabletop gaming interaction metaphors. In this paper, the authors discuss the heuristic lens that is used by the Meeple Centred Design tabletop accessibility project. This is a tool that has been applied to one hundred and sixteen games to date, and the full results of these have been published for analysis and consideration within the wider tabletop gaming community

Atomic structures of TDP-43 LCD segments and insights into reversible or pathogenic aggregation.

The normally soluble TAR DNA-binding protein 43 (TDP-43) is found aggregated both in reversible stress granules and in irreversible pathogenic amyloid. In TDP-43, the low-complexity domain (LCD) is believed to be involved in both types of aggregation. To uncover the structural origins of these two modes of β-sheet-rich aggregation, we have determined ten structures of segments of the LCD of human TDP-43. Six of these segments form steric zippers characteristic of the spines of pathogenic amyloid fibrils; four others form LARKS, the labile amyloid-like interactions characteristic of protein hydrogels and proteins found in membraneless organelles, including stress granules. Supporting a hypothetical pathway from reversible to irreversible amyloid aggregation, we found that familial ALS variants of TDP-43 convert LARKS to irreversible aggregates. Our structures suggest how TDP-43 adopts both reversible and irreversible β-sheet aggregates and the role of mutation in the possible transition of reversible to irreversible pathogenic aggregation

Planning a 'slum free' Trivandrum: housing upgrade and the rescaling of urban governance in India

This paper examines how India’s national urban development agenda is reshaping relationships between national, State and city-level governments. JNNURM, the flagship programme that heralded a new era of urban investment in India, contained a range of key governance aspirations: linking the analysis of urban poverty to city-level planning, developing holistic housing solutions for the urban poor, and above all empowering Urban Local Bodies to re-balance relationships between State and city-level governments in favour of the latter. Here, we trace JNNURM’s implementation in Kerala’s capital city, Trivandrum (Thiruvananthapuram), where the city’s decentralised urban governance structure and use of ‘pro-poor’ institutions to implement housing upgrade programmes could have made it an exemplar of success. In practice, Trivandrum’s ‘city visioning’ exercises and the housing projects it has undertaken have fallen short of JNNURM’s lofty goals. The contradictions between empowering cities and retaining centralised control embedded within this national programme, and the unintended city-level consequences of striving for JNNURM funding success, have reshaped urban governance in ways not envisaged within policy. As a result, JNNURM has been important in rescaling governance relationships through three interlinked dynamics of problem framing, technologies of governance and the scalar strategy of driving reform ‘from above’ that together have ensured the national state’s continued influence over the practices of urban governance in India

Network model of immune responses reveals key effectors to single and co-infection dynamics by a respiratory bacterium and a gastrointestinal helminth

Co-infections alter the host immune response but how the systemic and local processes at the site of infection interact is still unclear. The majority of studies on co-infections concentrate on one of the infecting species, an immune function or group of cells and often focus on the initial phase of the infection. Here, we used a combination of experiments and mathematical modelling to investigate the network of immune responses against single and co-infections with the respiratory bacterium Bordetella bronchiseptica and the gastrointestinal helminth Trichostrongylus retortaeformis. Our goal was to identify representative mediators and functions that could capture the essence of the host immune response as a whole, and to assess how their relative contribution dynamically changed over time and between single and co-infected individuals. Network-based discrete dynamic models of single infections were built using current knowledge of bacterial and helminth immunology; the two single infection models were combined into a co-infection model that was then verified by our empirical findings. Simulations showed that a T helper cell mediated antibody and neutrophil response led to phagocytosis and clearance of B. bronchiseptica from the lungs. This was consistent in single and co-infection with no significant delay induced by the helminth. In contrast, T. retortaeformis intensity decreased faster when co-infected with the bacterium. Simulations suggested that the robust recruitment of neutrophils in the co-infection, added to the activation of IgG and eosinophil driven reduction of larvae, which also played an important role in single infection, contributed to this fast clearance. Perturbation analysis of the models, through the knockout of individual nodes (immune cells), identified the cells critical to parasite persistence and clearance both in single and co-infections. Our integrated approach captured the within-host immuno-dynamics of bacteria-helminth infection and identified key components that can be crucial for explaining individual variability between single and co-infections in natural populations