Cultural Ecosystem Services: A Critical Assessment

This paper is about the practice of evaluating ecosystems on the basis of the cultural services they provide. My first aim is to assess the various objections that have been made to this practice. My second is to argue that when particular places are integral to people’s lives, their value cannot be adequately conceived in terms of the provision of cultural ecosystem services. It follows, I conclude, that the ecosystem services framework can provide only a very limited account of the value of places

The Trouble with Environmental Values

If we are to assess whether our attitudes towards nature are morally, aesthetically or in any other way appropriate or inappropriate, then we will need to know what those attitudes are. Drawing on the works of Katie McShane, Alan Holland and Christine Swanton, I challenge the common assumption that to love, respect, honour, cherish or adopt any other sort of pro-attitude towards any natural X simply is to value X in some way and to some degree. Depending on how one interprets ‘value’, that assumption is, I contend, either false or vacuous. I argue that to assess the appropriateness of a person’s pro-attitudes towards a natural entity one must in some cases appeal to the concepts of status and/or bond, and not just that of value. To develop my argument, I appeal to the works of two nature writers – Robert Macfarlane and J. A. Baker

Philistinism and the Preservation of Nature

It is clear that natural entities can be preserved – they can be preserved because they can be harmed or destroyed, or in various other ways adversely affected. I argue that in light of the rise of scientism and other forms of philistinism, the political, religious, mythic, personal and historical meanings that people find in those entities can also be preserved. Against those who impugn disciplines such as fine arts, philosophy and sociology, I contend that this sort of preservation requires the efforts of those whose work exemplifies the core values of the arts, the humanities and the qualitative social sciences

Protecting Nature for the Sake of Human Beings

It is often assumed that to say that nature should be protected for the sake of human beings just is to say that it should be protected because it is a means to one or more anthropocentric ends. I argue that this assumption is false. In some contexts, claims that a particular natural X should be protected for our sakes mean that X should be protected, not because it is a means to anthropocentric ends, but because it is part of something about human life that is of value: because, that is, its value is anthropocentric and constitutive rather than anthropocentric and instrumental. It follows, I suggest, that one does not need to endorse the non-anthropocentric claim that nature should be protected for its own sake in order to challenge the instrumentalist notion that it should be protected simply because it is a means to anthropocentric ends (as, say, a provider of ecosystem services). To make my case, I consider the UK Government's failed attempt to sell off England's publicly-owned forests

Legal Rights and Nature's Contributions to People: Is There a Connection?

It has been claimed that approaches to conservation framed in terms of nature’s contributions to people are congenial to ones framed in terms of rights. This paper provides what has so far been lacking – namely, an argument in support of this claim. The argument takes its cue from the observation that nature’s contributions to people can take the form of contributions to cultural identity. It is then argued that in some such cases one can justify conserving the relevant natural entities by appealing to the relevant people’s legal right to their own cultural identity. In such instances, it is proposed, appeals to nature’s contributions to people really are consonant with appeals to legal rights. The argument is developed by means of a discussion of the cultural value of reindeer herding in Saami communities in northern Europe

Finding - and Failing to Find - Meaning in Nature

This paper is about how we should evaluate our tendencies to find - or fail to find - different meanings in the natural world. It has three aims: (1) to show that some virtues and vices can be exhibited in our tendencies to find or to overlook the meanings of natural things, even if it is unclear whether any can only be exhibited in our relations with such things; (2) to categorise some of the relevant virtues and vices; and (3) to refute the objection that meaning-focused approaches to environmental philosophy, of the sort adopted by writers such as Alan Holland and myself, cannot adequately account for nature's independence from human concerns

Customizing the therapeutic response of signaling networks to promote antitumor responses by drug combinations

Drug resistance, de novo and acquired, pervades cellular signaling networks (SNs) from one signaling motif to another as a result of cancer progression and/or drug intervention. This resistance is one of the key determinants of efficacy in targeted anti-cancer drug therapy. Although poorly understood, drug resistance is already being addressed in combination therapy by selecting drug targets where SN sensitivity increases due to combination components or as a result of de novo or acquired mutations. Additionally, successive drug combinations have shown low resistance potential. To promote a rational, systematic development of combination therapies, it is necessary to establish the underlying mechanisms that drive the advantages of combination therapies, and design methods to determine drug targets for combination regimens. Based on a joint systems analysis of cellular SN response and its sensitivity to drug action and oncogenic mutations, we describe an in silico method to analyze the targets of drug combinations. Our method explores mechanisms of sensitizing the SN through a combination of two drugs targeting vertical signaling pathways. We propose a paradigm of SN response customization by one drug to both maximize the effect of another drug in combination and promote a robust therapeutic response against oncogenic mutations. The method was applied to customize the response of the ErbB/PI3K/PTEN/AKT pathway by combination of drugs targeting HER2 receptors and proteins in the down-stream pathway. The results of a computational experiment showed that the modification of the SN response from hyperbolic to smooth sigmoid response by manipulation of two drugs in combination leads to greater robustness in therapeutic response against oncogenic mutations determining cancer heterogeneity. The application of this method in drug combination co-development suggests a combined evaluation of inhibition effects together with the capability of drug combinations to suppress resistance mechanisms before they become clinically manifest

Kinetic modelling of in vitro data of PI3K, mTOR1, PTEN enzymes and on-target inhibitors Rapamycin, BEZ235, and LY294002

The phosphatidylinositide 3-kinases (PI3K) and mammalian target of rapamycin-1 (mTOR1) are two key targets for anti-cancer therapy. Predicting the response of the PI3K/AKT/mTOR1 signalling pathway to targeted therapy is made difficult because of network complexities. Systems biology models can help explore those complexities but the value of such models is dependent on accurate parameterisation. Motivated by a need to increase accuracy in kinetic parameter estimation, and therefore the predictive power of the model, we present a framework to integrate kinetic data from enzyme assays into a unified enzyme kinetic model. We present exemplar kinetic models of PI3K and mTOR1, calibrated on in vitro enzyme data and founded on Michaelis-Menten (MM) approximation. We describe the effects of an allosteric mTOR1 inhibitor (Rapamycin) and ATP-competitive inhibitors (BEZ2235 and LY294002) that show dual inhibition of mTOR1 and PI3K. We also model the kinetics of phosphatase and tensin homolog (PTEN), which modulates sensitivity of the PI3K/AKT/mTOR1 pathway to these drugs. Model validation with independent data sets allows investigation of enzyme function and drug dose dependencies in a wide range of experimental conditions. Modelling of the mTOR1 kinetics showed that Rapamycin has an IC50 independent of ATP concentration and that it is a selective inhibitor of mTOR1 substrates S6K1 and 4EBP1: it retains 40% of mTOR1 activity relative to 4EBP1 phosphorylation and inhibits completely S6K1 activity. For the dual ATP-competitive inhibitors of mTOR1 and PI3K, LY294002 and BEZ235, we derived the dependence of the IC50 on ATP concentration that allows prediction of the IC50 at different ATP concentrations in enzyme and cellular assays. Comparison of the drug effectiveness in enzyme and cellular assays showed that some features of these drugs arise from signalling modulation beyond the on-target action and MM approximation and require a systems-level consideration of the whole PI3K/PTEN/AKT/mTOR1 network in order to understand mechanisms of drug sensitivity and resistance in different cancer cell lines. We suggest that using these models in systems biology investigation of the PI3K/AKT/mTOR1 signalling in cancer cells can bridge the gap between direct drug target action and the therapeutic response to these drugs and their combinations

Bleomycin increases neutrophil adhesion to human vascular endothelial cells independently of upregulation of ICAM-1 and E-selectin

© 2016 Taylor & Francis. Aim of the Study: Bleomycin-induced lung disease is a serious complication of therapy characterized by alveolar injury, cytokine release, inflammatory cell recruitment, and eventually pulmonary fibrosis. The mechanisms underlying bleomycin-induced pulmonary fibrosis may be relevant to other progressive scarring diseases of the lungs. Pulmonary vascular endothelial cells are critically involved in immune cell extravasation at sites of injury through adhesion molecule expression and cytokine release. We sought to determine the effects of bleomycin on adhesion molecule expression and cytokine release by pulmonary vascular endothelial cells, and their functional relevance to inflammatory cell recruitment. Materials and Methods: The effects of pharmacologically relevant concentrations of bleomycin on adhesion molecule expression and cytokine release by human vascular endothelial cells in vitro were studied by flow cytometry, quantitative polymerase chain reaction, and enzyme-linked immunosorbent assay. A flow chamber model was used to assess the functional consequences on adhesion of flowing human neutrophils to endothelial cell monolayers. Results: Bleomycin increased intercellular adhesion molecule 1 (ICAM-1; CD54), vascular cell adhesion molecule (VCAM-1; CD106), and E-selectin (CD62E) expression, and increased monocyte chemoattractant protein (MCP-1) and interleukin (IL-8) release by endothelial cells. Increases in protein expression were accompanied by increased mRNA transcription. In contrast, there was no direct effect of bleomycin on the profibrotic cytokines transforming growth factor-beta (TGF-β), platelet-derived growth factor-BB (PDGF-BB), or endothelin-1. Under flow conditions, endothelial cells exposed to bleomycin supported increased neutrophil adhesion which was independent of ICAM-1 or E-selectin. Conclusion: Our findings demonstrate that bleomycin promotes endothelial-mediated inflammation and neutrophil adhesion. These mechanisms may contribute to the development of pulmonary fibrosis by supporting immune cell recruitment in the lungs