Metabolic exhaustion in infection, cancer and autoimmunity

It has become increasingly clear that changes in metabolism are not just consequences of T cell activation but instead are also essential drivers of that process that shape the extent and nature of differentiation and function. The process of T cell exhaustion has been linked to the outcome of chronic immune responses in multiple contexts, including chronic infection, cancer and autoimmunity. Factors that regulate the development and maintenance of exhaustion are of increasing interest as targets of therapeutic modulation. Studies have shown T cell immunometabolism to be integral to the control and development of T cell exhaustion. Early metabolic changes are responsible for the later emergence of exhaustion, do not simply reflect changes secondary to chronic activation and are modifiable. Increased understanding of this metabolic control promises to improve the ability to modulate T cell immunity to chronic antigen stimulation in multiple contexts

Myofibroblast androgen receptor expression determines cell survival in co-cultures of myofibroblasts and prostate cancer cells in vitro.

Fibroblasts express androgen receptor (AR) in the normal prostate and during prostate cancer development. We have reported that loss of AR expression in prostate cancer-associated fibroblasts is a poor prognostic indicator. Here we report outcomes of direct and indirect co-cultures of immortalised AR-positive (PShTert-AR) or AR-negative (PShTert) myofibroblasts with prostate cancer cells. In the initial co-cultures the AR-negative PC3 cell line was used so AR expression and signalling were restricted to the myofibroblasts. In both direct and indirect co-culture with PShTert-AR myofibroblasts, paracrine signalling to the PC3 cells slowed proliferation and induced apoptosis. In contrast, PC3 cells proliferated with PShTert myofibroblasts irrespective of the co-culture method. In direct co-culture PC3 cells induced apoptosis in and destroyed PShTerts by direct signalling. Similar results were seen in direct co-cultures with AR-negative DU145 and AR-positive LNCaP and C4-2B prostate cancer cell lines. The AR ligand 5α-dihydrotestosterone (DHT) inhibited the proliferation of the PShTert-AR myofibroblasts, thereby reducing the extent of their inhibitory effect on cancer cell growth. These results suggest loss of stromal AR would favour prostate cancer cell growth in vivo, providing an explanation for the clinical observation that reduced stromal AR is associated with a poorer outcome

The future of coral reefs subject to rapid climate change: Lessons from natural extreme environments

Global climate change and localized anthropogenic stressors are driving rapid declines in coral reef health. In vitro experiments have been fundamental in providing insight into how reef organisms will potentially respond to future climates. However, such experiments are inevitably limited in their ability to reproduce the complex interactions that govern reef systems. Studies examining coral communities that already persist under naturally-occurring extreme and marginal physicochemical conditions have therefore become increasingly popular to advance ecosystem scale predictions of future reef form and function, although no single site provides a perfect analog to future reefs. Here we review the current state of knowledge that exists on the distribution of corals in marginal and extreme environments, and geographic sites at the latitudinal extremes of reef growth, as well as a variety of shallow reef systems and reef-neighboring environments (including upwelling and CO 2 vent sites). We also conduct a synthesis of the abiotic data that have been collected at these systems, to provide the first collective assessment on the range of extreme conditions under which corals currently persist. We use the review and data synthesis to increase our understanding of the biological and ecological mechanisms that facilitate survival and success under sub-optimal physicochemical conditions. This comprehensive assessment can begin to: (i) highlight the extent of extreme abiotic scenarios under which corals can persist, (ii) explore whether there are commonalities in coral taxa able to persist in such extremes, (iii) provide evidence for key mechanisms required to support survival and/or persistence under sub-optimal environmental conditions, and (iv) evaluate the potential of current sub-optimal coral environments to act as potential refugia under changing environmental conditions. Such a collective approach is critical to better understand the future survival of corals in our changing environment. We finally outline priority areas for future research on extreme and marginal coral environments, and discuss the additional management options they may provide for corals through refuge or by providing genetic stocks of stress tolerant corals to support proactive management strategies

Demanding stories: television coverage of sustainability, climate change and material demand

This paper explores the past, present and future role of broadcasting, above all via the medium of television, in shaping how societies talk, think about and act on climate change and sustainability issues. The paper explores these broad themes via a focus on the important but relatively neglected issue of material demand and opportunities for its reduction. It takes the outputs and decision-making of one of the world’s most influential broadcasters, the BBC, as its primary focus. The paper considers these themes in terms of stories, touching on some of the broader societal frames of understanding into which they can be grouped. Media decision-makers and producers from a range of genres frequently return to the centrality of ‘story’ in the development, commissioning and production of an idea. With reference to specific examples of programming, and drawing on interviews with media practitioners, the paper considers the challenges of generating broadcast stories that can inspire engagement in issues around climate change, and specifically material demand. The concluding section proposes actions and approaches that might help to establish material demand reduction as a prominent way of thinking about climate change and environmental issues more widely. This article is part of the themed issue ‘Material demand reduction’

The XIIIth Banff Conference on Allograft Pathology: The Banff 2015 Heart Meeting Report: Improving Antibody-Mediated Rejection Diagnostics: Strengths, Unmet Needs, and Future Directions.

The 13th Banff Conference on Allograft Pathology was held in Vancouver, British Columbia, Canada from October 5 to 10, 2015. The cardiac session was devoted to current diagnostic issues in heart transplantation with a focus on antibody-mediated rejection (AMR) and small vessel arteriopathy. Specific topics included the strengths and limitations of the current rejection grading system, the central role of microvascular injury in AMR and approaches to semiquantitative assessment of histopathologic and immunophenotypic indicators, the role of AMR in the development of cardiac allograft vasculopathy, the important role of serologic antibody detection in the management of transplant recipients, and the potential application of new molecular approaches to the elucidation of the pathophysiology of AMR and potential for improving the current diagnostic system. Herein we summarize the key points from the presentations, the comprehensive, open and wide-ranging multidisciplinary discussion that was generated, and considerations for future endeavors

Reef-building corals thrive within hot-acidified and deoxygenated waters

© The Author(s) 2017. Coral reefs are deteriorating under climate change as oceans continue to warm and acidify and thermal anomalies grow in frequency and intensity. In vitro experiments are widely used to forecast reef-building coral health into the future, but often fail to account for the complex ecological and biogeochemical interactions that govern reefs. Consequently, observations from coral communities under naturally occurring extremes have become central for improved predictions of future reef form and function. Here, we present a semi-enclosed lagoon system in New Caledonia characterised by diel fluctuations of hot-deoxygenated water coupled with tidally driven persistently low pH, relative to neighbouring reefs. Coral communities within the lagoon system exhibited high richness (number of species = 20) and cover (24-35% across lagoon sites). Calcification rates for key species (Acropora formosa, Acropora pulchra, Coelastrea aspera and Porites lutea) for populations from the lagoon were equivalent to, or reduced by ca. 30-40% compared to those from the reef. Enhanced coral respiration, alongside high particulate organic content of the lagoon sediment, suggests acclimatisation to this trio of temperature, oxygen and pH changes through heterotrophic plasticity. This semi-enclosed lagoon therefore provides a novel system to understand coral acclimatisation to complex climatic scenarios and may serve as a reservoir of coral populations already resistant to extreme environmental conditions

A novel membrane inlet-infrared gas analysis (MI-IRGA) system for monitoring of seawater carbonate system

Increased atmospheric CO 2 concentrations are driving changes in ocean chemistry at unprecedented rates resulting in ocean acidification, which is predicted to impact the functioning of marine biota, in particular of marine calcifiers. However, the precise understanding of such impacts relies on an analytical system that determines the mechanisms and impact of elevated pCO 2 on the physiology of organisms at scales from species to entire communities. Recent work has highlighted the need within experiments to control all aspects of the carbonate system to resolve the role of different inorganic carbon species on the physiological responses observed across taxa in real-time. Presently however, there are limited options available for continuous quantification of physiological responses, coupled with real-time calculation of the seawater carbonate chemistry system within microcosm environments. Here, we describe and characterise the performance of a novel pCO 2 membrane equilibrium system (the Membrane Inlet Infra-Red Gas Analyser, MI-IRGA) integrated with a continuous pH and oxygen monitoring platform. The system can detect changes in the seawater carbonate chemistry and determine organism physiological responses, while providing the user with real-time control over the microcosm system. We evaluate the systems control, response time and associated error, and demonstrate the flexibility of the system to operate under field conditions and within a laboratory. We use the system to measure physiological parameters (photosynthesis and respiration) for the corals Pocillipora damicornis and Porites cylindrica; in doing so we present a novel dataset examining the interactive role of temperature, light and pCO 2 on the physiology of P. cylindrica

Bone marrow mesenchymal stem cells do not enhance intra-synovial tendon healing despite engraftment and homing to niches within the synovium

Intra-synovial tendon injuries display poor healing, which often results in reduced functionality and pain. A lack of effective therapeutic options has led to experimental approaches to augment natural tendon repair with autologous mesenchymal stem cells (MSCs) although the effects of the intra-synovial environment on the distribution, engraftment and functionality of implanted MSCs is not known. This study utilised a novel sheep model which, although in an anatomically different location, more accurately mimics the mechanical and synovial environment of the human rotator cuff, to determine the effects of intra-synovial implantation of MSCs