Decreased glutathione biosynthesis contributes to EGFR T790M-driven erlotinib resistance in non-small cell lung cancer

Epidermal growth factor receptor (EGFR) inhibitors such as erlotinib are novel effective agents in the treatment of EGFR-driven lung cancer, but their clinical impact is often impaired by acquired drug resistance through the secondary T790M EGFR mutation. To overcome this problem, we analysed the metabonomic differences between two independent pairs of erlotinib-sensitive/resistant cells and discovered that glutathione (GSH) levels were significantly reduced in T790M EGFR cells. We also found that increasing GSH levels in erlotinib-resistant cells re-sensitised them, whereas reducing GSH levels in erlotinib-sensitive cells made them resistant. Decreased transcription of the GSH-synthesising enzymes (GCLC and GSS) due to the inhibition of NRF2 was responsible for low GSH levels in resistant cells that was directly linked to the T790M mutation. T790M EGFR clinical samples also showed decreased expression of these key enzymes; increasing intra-tumoural GSH levels with a small-molecule GST inhibitor re-sensitised resistant tumours to erlotinib in mice. Thus, we identified a new resistance pathway controlled by EGFR T790M and a therapeutic strategy to tackle this problem in the clinic

Reports from the Fifth EAHN Meeting in Tallinn

The fifth international meeting of the European Architectural History Network was held in Tallinn, at the National Library of Estonia, from 13 to 16 June 2018. The reports from this meeting aim to capture some of the main themes that came up during four intense days of academic discussions and exchange, meetings, and free-form interaction in different spatial and social settings. After the introduction by Andres Kurg, host of the Tallinn Meeting, five delegates review the five thematic tracks which organised the selected sessions and ran in parallel throughout the three days of the conference: Mediations, Comparative Modernities, Peripheries, Discovery and Persistence, and Body and Mind. In his closing keynote lecture, Reinhold Martin from Columbia University further reflected on the ample critical discussions which had taken place throughout the conference

Towards a synthesized critique of neoliberal biodiversity conservation

During the last three decades, the arena of biodiversity conservation has largely aligned itself with the globally dominant political ideology of neoliberalism and associated governmentalities. Schemes such as payments for ecological services are promoted to reach the multiple ‘wins’ so desired: improved biodiversity conservation, economic development, (international) cooperation and poverty alleviation, amongst others. While critical scholarship with respect to understanding the linkages between neoliberalism, capitalism and the environment has a long tradition, a synthesized critique of neoliberal conservation - the ideology (and related practices) that the salvation of nature requires capitalist expansion - remains lacking. This paper aims to provide such a critique. We commence with the assertion that there has been a conflation between ‘economics’ and neoliberal ideology in conservation thinking and implementation. As a result, we argue, it becomes easier to distinguish the main problems that neoliberal win-win models pose for biodiversity conservation. These are framed around three points: the stimulation of contradictions; appropriation and misrepresentation and the disciplining of dissent. Inspired by Bruno Latour’s recent ‘compositionist manifesto’, the conclusion outlines some ideas for moving beyond critique

Shadowing in the nuclear photoabsorption above the resonance region

A model based on the hadronic fluctuations of the real photon is developed to describe the total photonucleon and photonuclear cross sections in the energy region above the nucleon resonances. The hadronic spectral function of the photon is derived including the finite width of vector-meson resonances and the quark-antiquark continuum. The shadowing effect is evaluated considering the effective interaction of the hadronic component with the bound nucleons within a Glauber-Gribov multiple scattering theory. The low energy onset of the shadowing effect is interpreted as a possible signature of a modification of the hadronic spectral function in the nuclear medium. A decrease of the $\rho$-meson mass in nuclei is suggested for a better explanation of the experimental data.Comment: 8 pages, 7 figure

Normalising jurisdictional heterotopias through place branding : the cases of Christiania and Metelkova

This paper explores the political dimensions of place branding as a path to normalisation for areas where a paradoxical relationship with the law exists, places that we coin “jurisdictional heterotopias” borrowing from Foucauldian literature. We posit that place branding plays a fundamental role in facilitating scale jumping in the otherwise vertically aligned legal space, a hierarchy designed to exclude spatial multiplicity from its premise. By examining the role of place branding in such areas, we endeavour to understand and appreciate the selective application of the law, the perpetuation of unregulated and illegal activity, as well as the place – specificity of legal practice. Ultimately, we argue that strong place branding associations permit the engulfment of this type of heterotopias in the “mainstream” leading to their normalisation; such a normalisation results not only in the acceptance of their uniqueness by the institutional elements, but also in the potential nullification of the liberties their communities advocate

State based model of long-term potentiation and synaptic tagging and capture

Recent data indicate that plasticity protocols have not only synapse-specific but also more widespread effects. In particular, in synaptic tagging and capture (STC), tagged synapses can capture plasticity-related proteins, synthesized in response to strong stimulation of other synapses. This leads to long-lasting modification of only weakly stimulated synapses. Here we present a biophysical model of synaptic plasticity in the hippocampus that incorporates several key results from experiments on STC. The model specifies a set of physical states in which a synapse can exist, together with transition rates that are affected by high- and low-frequency stimulation protocols. In contrast to most standard plasticity models, the model exhibits both early- and late-phase LTP/D, de-potentiation, and STC. As such, it provides a useful starting point for further theoretical work on the role of STC in learning and memory

Radical, Reformist, and Garden-Variety Neoliberal: Coming to Terms with Urban Agriculture’s Contradictions

For many activists and scholars, urban agriculture in the Global North has become synonymous with sustainable food systems, standing in opposition to the dominant industrial agri-food system. At the same time, critical social scientists increasingly argue that urban agriculture programmes, by filling the void left by the rolling back of the social safety net, underwrite neoliberalisation. I argue that such contradictions are central to urban agriculture. Drawing on existing literature and fieldwork in Oakland, CA, I explain how urban agriculture arises from a protective counter-movement, while at the same time entrenching the neoliberal organisation of contemporary urban political economies through its entanglement with multiple processes of neoliberalisation. By focusing on one function or the other, however, rather than understanding such contradictions as internal and inherent, we risk undermining urban agriculture\u27s transformative potential. Coming to terms with its internal contradictions can help activists, policy-makers and practitioners better position urban agriculture within coordinated efforts for structural change, one of many means to an end rather than an end unto itself

Label-Free Phenotypic Profiling Identified D-Luciferin as a GPR35 Agonist

Fluorescent and luminescent probes are essential to both in vitro molecular assays and in vivo imaging techniques, and have been extensively used to measure biological function. However, little is known about the biological activity, thus potential interferences with the assay results, of these probe molecules. Here we show that D-luciferin, one of the most widely used bioluminescence substrates, is a partial agonist for G protein-coupled receptor-35 (GPR35). Label-free phenotypic profiling using dynamic mass redistribution (DMR) assays showed that D-luciferin led to a DMR signal in native HT-29 cells, whose characteristics are similar to those induced by known GPR35 agonists including zaprinast and pamoic acid. DMR assays further showed that D-luciferin is a partial agonist competitive to several known GPR35 agonists and antagonists. D-luciferin was found to cause the phosphorylation of ERK that was suppressed by known GPR35 antagonists, and also result in β-arrestin translocation signal but with low efficacy. These results not only suggest that D-luciferin is a partial agonist of GPR35, but also will evoke careful interpretation of biological data obtained using molecular and in vivo imaging assays when these probe molecules are used

Modelling credit spreads with time volatility, skewness, and kurtosis

This paper seeks to identify the macroeconomic and financial factors that drive credit spreads on bond indices in the US credit market. To overcome the idiosyncratic nature of credit spread data reflected in time varying volatility, skewness and thick tails, it proposes asymmetric GARCH models with alternative probability density functions. The results show that credit spread changes are mainly explained by the interest rate and interest rate volatility, the slope of the yield curve, stock market returns and volatility, the state of liquidity in the corporate bond market and, a heretofore overlooked variable, the foreign exchange rate. They also confirm that the asymmetric GARCH models and Student-t distributions are systematically superior to the conventional GARCH model and the normal distribution in in-sample and out-of-sample testing