Genetic partitioning of interleukin-6 signalling in mice dissociates Stat3 from Smad3-mediated lung fibrosis

Idiopathic pulmonary fibrosis (IPF) is a fatal disease that is unresponsive to current therapies and characterized by excessive collagen deposition and subsequent fibrosis. While inflammatory cytokines, including interleukin (IL)-6, are elevated in IPF, the molecular mechanisms that underlie this disease are incompletely understood, although the development of fibrosis is believed to depend on canonical transforming growth factor (TGF)-β signalling. We examined bleomycin-induced inflammation and fibrosis in mice carrying a mutation in the shared IL-6 family receptor gp130. Using genetic complementation, we directly correlate the extent of IL-6-mediated, excessive Stat3 activity with inflammatory infiltrates in the lung and the severity of fibrosis in corresponding gp130757F mice. The extent of fibrosis was attenuated in B lymphocyte-deficient gp130757F;µMT−/− compound mutant mice, but fibrosis still occurred in their Smad3−/− counterparts consistent with the capacity of excessive Stat3 activity to induce collagen 1α1 gene transcription independently of canonical TGF-β/Smad3 signalling. These findings are of therapeutic relevance, since we confirmed abundant STAT3 activation in fibrotic lungs from IPF patients and showed that genetic reduction of Stat3 protected mice from bleomycin-induced lung fibrosis

Strain‐Promoted Cycloadditions in Lipid Bilayers Triggered by Liposome Fusion

Due to the variety of roles served by the cell membrane, its composition and structure are complex, making it difficult to study. Bioorthogonal reactions, such as the strain promoted azide-alkyne cycloaddition (SPAAC), are powerful tools for exploring the function of biomolecules in their native environment but have been largely unexplored within the context of lipid bilayers. Here, we developed a new approach to study the SPAAC reaction in liposomal membranes using azide- and strained alkyne-functionalized Förster resonance energy transfer (FRET) dye pairs. This study represents the first characterization of the SPAAC reaction between diffusing molecules inside liposomal membranes. Potential applications of this work include in situ bioorthogonal labeling of membrane proteins, improved understanding of membrane dynamics and fluidity, and the generation of new probes for biosensing assays

Comment on: “Peatland carbon stocks and burn history: Blanket bog peat core evidence highlights charcoal impacts on peat physical properties and long-term carbon storage”, by A. Heinemeyer, Q. Asena, W.L. Burn and A.L. Jones (Geo: Geography and Environment. 2018; e00063)

A recent paper by Heinemeyer et al. (2018) in this journal has suggested that the use of prescribed fire may enhance carbon accumulation in UK upland blanket bogs. We challenge this finding based on a number of concerns with the original manuscript including the lack of an unburned control, insufficient replication, unrecognised potential confounding factors, and potentially large inaccuracies in the core dating approach used to calculate carbon accumulation rates. We argue that burn‐management of peatlands is more likely to lead to carbon loss than carbon gain

Playing the game: service users' management of risk status in a UK medium secure forensic mental health service

In this article we examine how forensic mental health service users actively attempt to manage their risk status through playing the game of containing frustration and demonstrating compliance. The article draws on an observational study (2006 to 2009) which explored the practices of risk assessment and management within one inner city forensic mental health medium secure service in the UK. We used a grounded theory approach to explore service users and providers experiences of risk assessment and management. We interviewed forensic mental health service users and providers. We also collected data using participant and non-participant observation. Since access to forensic mental health services is tightly controlled, there are participant observation studies undertaken in these settings. We found that service users attempted to understand the system of assessment and sought to affect and reduce their risk status by engaging in overt, compliant behaviours. We argue that in doing so service users are active agents in the process of risk management. However, we indicate that there are adverse effects of this approach to risk management as the risk assessment process is subverted by the restriction of the flow of information, and service users are left with frustrations that they must contain and manage

Active Amplification of the Terrestrial Albedo to Mitigate Climate Change: An Exploratory Study

This study explores the potential to enhance the reflectance of solar insolation by the human settlement and grassland components of the Earth's terrestrial surface as a climate change mitigation measure. Preliminary estimates derived using a static radiative transfer model indicate that such efforts could amplify the planetary albedo enough to offset the current global annual average level of radiative forcing caused by anthropogenic greenhouse gases by as much as 30 percent or 0.76 W/m2. Terrestrial albedo amplification may thus extend, by about 25 years, the time available to advance the development and use of low-emission energy conversion technologies which ultimately remain essential to mitigate long-term climate change. However, additional study is needed to confirm the estimates reported here and to assess the economic and environmental impacts of active land-surface albedo amplification as a climate change mitigation measure.Comment: 21 pages, 3 figures. In press with Mitigation and Adaptation Strategies for Global Change, Springer, N

Opportunities for advances in climate change economics

There have been dramatic advances in understanding the physical science of climate change, facilitated by substantial and reliable research support. The social value of these advances depends on understanding their implications for society, an arena where research support has been more modest and research progress slower. Some advances have been made in understanding and formalizing climate-economy linkages, but knowledge gaps remain [e.g., as discussed in (1, 2)]. We outline three areas where we believe research progress on climate economics is both sorely needed, in light of policy relevance, and possible within the next few years given appropriate funding: (i) refining the social cost of carbon (SCC), (ii) improving understanding of the consequences of particular policies, and (iii) better understanding of the economic impacts and policy choices in developing economies

Metabolite profiles of medulloblastoma for rapid and non-invasive detection of molecular disease groups

BackgroundThe malignant childhood brain tumour, medulloblastoma, is classified clinically into molecular groups which guide therapy. DNA-methylation profiling is the current classification ‘gold-standard’, typically delivered 3–4 weeks post-surgery. Pre-surgery non-invasive diagnostics thus offer significant potential to improve early diagnosis and clinical management. Here, we determine tumour metabolite profiles of the four medulloblastoma groups, assess their diagnostic utility using tumour tissue and potential for non-invasive diagnosis using in vivo magnetic resonance spectroscopy (MRS).MethodsMetabolite profiles were acquired by high-resolution magic-angle spinning NMR spectroscopy (MAS) from 86 medulloblastomas (from 59 male and 27 female patients), previously classified by DNA-methylation array (WNT (n = 9), SHH (n = 22), Group3 (n = 21), Group4 (n = 34)); RNA-seq data was available for sixty. Unsupervised class-discovery was performed and a support vector machine (SVM) constructed to assess diagnostic performance. The SVM classifier was adapted to use only metabolites (n = 10) routinely quantified from in vivo MRS data, and re-tested. Glutamate was assessed as a predictor of overall survival.FindingsGroup-specific metabolite profiles were identified; tumours clustered with good concordance to their reference molecular group (93%). GABA was only detected in WNT, taurine was low in SHH and lipids were high in Group3. The tissue-based metabolite SVM classifier had a cross-validated accuracy of 89% (100% for WNT) and, adapted to use metabolites routinely quantified in vivo, gave a combined classification accuracy of 90% for SHH, Group3 and Group4. Glutamate predicted survival after incorporating known risk-factors (HR = 3.39, 95% CI 1.4–8.1, p = 0.025).InterpretationTissue metabolite profiles characterise medulloblastoma molecular groups. Their combination with machine learning can aid rapid diagnosis from tissue and potentially in vivo. Specific metabolites provide important information; GABA identifying WNT and glutamate conferring poor prognosis

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

Distribution and characteristics of overdeepenings beneath the Greenland and Antarctic ice sheets: Implications for overdeepening origin and evolution

Glacier bed overdeepenings are ubiquitous in glacier systems and likely exert significant influence on ice dynamics, subglacial hydrology, and ice stability. Understanding of overdeepening formation and evolution has been hampered by an absence of quantitative empirical studies of their location and morphology, with process insights having been drawn largely from theoretical or numerical studies. To address this shortcoming, we first map the distribution of potential overdeepenings beneath the Antarctic and Greenland ice sheets using a GIS-based algorithm that identifies closed-contours in the bed topography and then describe and analyse the characteristics and metrics of a subset of overdeepenings that pass further quality control criteria. Overdeepenings are found to be widespread, but are particularly associated with areas of topographically laterally constrained ice flow, notably near the ice sheet margins where outlet systems follow deeply incised troughs. Overdeepenings also occur in regions of topographically unconstrained ice flow (for example, beneath the Siple Coast ice streams and on the Greenland continental shelf). Metrics indicate that overdeepening growth is generally allometric and that topographic confinement of ice flow in general enhances overdeepening depth. However, overdeepening depth is skewed towards shallow values – typically 200 to 300 m – indicating that the rate of deepening slows with overdeepening age. This is reflected in a decline in adverse slope steepness with increasing overdeepening planform size. Finally, overdeepening long-profiles are found to support headward quarrying as the primary factor in overdeepening development. These observations support proposed negative feedbacks related to hydrology and sediment transport that stabilise overdeepening growth through sedimentation on the adverse slope but permit continued overdeepening planform enlargement by processes of headward erosion