Disrupted in schizophrenia 1 and synaptic function in the mammalian central nervous system

This is the final version of the article. Available from the publisher via the DOI in this record.The disrupted in schizophrenia 1 (DISC1) gene is found at the breakpoint of an inherited chromosomal translocation, and segregates with major mental illnesses. Its potential role in central nervous system (CNS) malfunction has triggered intensive investigation of the biological roles played by DISC1, with the hope that this may shed new light on the pathobiology of psychiatric disease. Such work has ranged from investigations of animal behavior to detailed molecular-level analysis of the assemblies that DISC1 forms with other proteins. Here, we discuss the evidence for a role of DISC1 in synaptic function in the mammalian CNS.M. Kurihara was supported by a Medical Research Council Industrial collaborative studentship in collaboration with Pfizer, who also supported aspects of DISC1-related work in A. D. Randall’s laborator

Characterising the distribution of methane and carbon dioxide emissions from the natural gas supply chain

Methane and CO2 emissions from the natural gas supply chain have been shown to vary widely but there is little understanding about the distribution of emissions across supply chain routes, processes, regions and operational practises. This study defines the distribution of total methane and CO2 emissions from the natural gas supply chain, identifying the contribution from each stage and quantifying the effect of key parameters on emissions. The study uses recent high-resolution emissions measurements with estimates of parameter distributions to build a probabilistic emissions model for a variety of technological supply chain scenarios. The distribution of emissions resembles a log-log-logistic distribution for most supply chain scenarios, indicating an extremely heavy tailed skew: median estimates which represent typical facilities are modest at 18 – 24 g CO2 eq./ MJ HHV, but mean estimates which account for the heavy tail are 22 – 107 g CO2 eq./ MJ HHV. To place these values into context, emissions associated with natural gas combustion (e.g. for heat) are approximately 55 g CO2/ MJ HHV. Thus, some supply chain scenarios are major contributors to total greenhouse gas emissions from natural gas. For methane-only emissions, median estimates are 0.8 – 2.2% of total methane production, with mean emissions of 1.6 - 5.5%. The heavy tail distribution is the signature of the disproportionately large emitting equipment known as super-emitters, which appear at all stages of the supply chain. The study analyses the impact of different technological options and identifies a set of best technological option (BTO) scenarios. This suggests that emissions-minimising technology can reduce supply chain emissions significantly, with this study estimating median emissions of 0.9% of production. However, even with the emissions-minimising technologies, evidence suggests that the influence of the super-emitters remains. Therefore, emissions-minimising technology is only part of the solution: reducing the impact of super emitters requires more effective detection and rectification, as well as pre-emptive maintenance processes

Impact of drilling costs on the US gas industry: prospects for automation

Recent low gas prices have greatly increased pressure on drilling companies to reduce costs and increase efficiency. Field trials have shown that implementing automation can dramatically reduce drilling costs by reducing the time required to drill wells. This study uses the DYNamic upstreAm gAs MOdel (DYNAAMO), a new techno-economic, bottom-up model of natural gas supply, to quantitatively assess the economic impact of lower drilling costs on the US upstream gas industry. A sensitivity analysis of three key economic indicators is presented, with results quoted for the most common field types currently producing, including unconventional and offshore gas. While all operating environments show increased profitability from drilling automation, it is found that conventional onshore reserves can benefit to the greatest extent. For large gas fields, a 50% reduction in drilling costs is found to reduce initial project breakevens by up to 17 million USD per billion cubic metres (MUSD/BCM) and mid-plateau breakevens by up to 8 MUSD/BCM. In this same scenario, additional volumes of around 160 BCM of unconventional gas are shown to become commercial due to both the lower costs of additional production wells in mature fields and the viability of developing new resources held in smaller fields. The capital efficiency of onshore projects increases by 50%-100%, with initial project net present value (NPV) gains of up to 32%

Assessing the impact of future greenhouse gas emissions from natural gas production

Greenhouse gases (GHGs) produced by the extraction of natural gas are an important contributor to lifecycle emissions and account for a significant fraction of anthropogenic methane emissions in the USA. The timing as well as the magnitude of these emissions matters, as the short term climate warming impact of methane is up to 120 times that of CO 2 . This study uses estimates of CO 2 and methane emissions associated with different upstream operations to build a deterministic model of GHG emissions from conventional and unconventional gas fields as a function of time. By combining these emissions with a dynamic, techno-economic model of gas supply we assess their potential impact on the value of different types of project and identify stranded resources in various carbon price scenarios. We focus in particular on the effects of different emission metrics for methane, using the global warming potential (GWP) and the global temperature potential (GTP), with both fixed 20-year and 100-year CO 2 -equivalent values and in a time-dependent way based on a target year for climate stabilisation. We report a strong time dependence of emissions over the lifecycle of a typical field, and find that bringing forward the stabilisation year dramatically increases the importance of the methane contribution to these emissions. Using a commercial database of the remaining reserves of individual projects, we use our model to quantify future emissions resulting from the extraction of current US non-associated reserves. A carbon price of at least 400 USD/tonne CO 2 is effective in reducing cumulative GHGs by 30–60%, indicating that decarbonising the upstream component of the natural gas supply chain is achievable using carbon prices similar to those needed to decarbonise the energy system as a whole. Surprisingly, for large carbon prices, the choice of emission metric does not have a significant impact on cumulative emissions

Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses.

Mesenchymal tumor subpopulations secrete pro-tumorigenic cytokines and promote treatment resistance1-4. This phenomenon has been implicated in chemorefractory small cell lung cancer and resistance to targeted therapies5-8, but remains incompletely defined. Here, we identify a subclass of endogenous retroviruses (ERVs) that engages innate immune signaling in these cells. Stimulated 3 prime antisense retroviral coding sequences (SPARCS) are oriented inversely in 3' untranslated regions of specific genes enriched for regulation by STAT1 and EZH2. Derepression of these loci results in double-stranded RNA generation following IFN-γ exposure due to bi-directional transcription from the STAT1-activated gene promoter and the 5' long terminal repeat of the antisense ERV. Engagement of MAVS and STING activates downstream TBK1, IRF3, and STAT1 signaling, sustaining a positive feedback loop. SPARCS induction in human tumors is tightly associated with major histocompatibility complex class 1 expression, mesenchymal markers, and downregulation of chromatin modifying enzymes, including EZH2. Analysis of cell lines with high inducible SPARCS expression reveals strong association with an AXL/MET-positive mesenchymal cell state. While SPARCS-high tumors are immune infiltrated, they also exhibit multiple features of an immune-suppressed microenviroment. Together, these data unveil a subclass of ERVs whose derepression triggers pathologic innate immune signaling in cancer, with important implications for cancer immunotherapy

Exploring research institutes: Structures, functioning and typology

Research institutes play an important role as part of the innovation landscape, which includes industrial, academic and governmental organisations. Although there is often much confusion over what constitutes an institute and there can even be a number of different terms associated with such organisational forms, including centres, networks, programmes and laboratories. Indeed institutes can enable multidisciplinary research and the translation of knowledge generated to deliver societal benefits and address industrial requirements. However, despite the benefits offered by establishing research institutes, there has been a distinct lack of studies in this area. Therefore, this paper provides the findings from an initial research study into the structure, functioning and typology of institutes. Following a literature review on institutes, a benchmarking study involving examination of 25 research institutes associated with the energy sector has been carried out. This study identified key features of the institutes, in regard to the research area, technology readiness level, funding, partners, organisational structure, leadership and governance arrangements. Subsequent analysis of these findings has resulted in three main types of institute being identified. The pros and cons for each institute type are provided along with recommendations on the development and management of research institutes

Nickel and helium evidence for melt above the core–mantle boundary

High ^(3)He/^(4)He ratios in some basalts have generally been interpreted as originating in an incompletely degassed lower-mantle source. This helium source may have been isolated at the core–mantle boundary region since Earth’s accretion. Alternatively, it may have taken part in whole-mantle convection and crust production over the age of the Earth; if so, it is now either a primitive refugium at the core–mantle boundary or is distributed throughout the lower mantle. Here we constrain the problem using lavas from Baffin Island, West Greenland, the Ontong Java Plateau, Isla Gorgona and Fernandina (Galapagos). Olivine phenocryst compositions show that these lavas originated from a peridotite source that was about 20 per cent higher in nickel content than in the modern mid-ocean-ridge basalt source. Where data are available, these lavas also have high ^(3)He/^(4)He. We propose that a less-degassed nickel-rich source formed by core–mantle interaction during the crystallization of a melt-rich layer or basal magma ocean, and that this source continues to be sampled by mantle plumes. The spatial distribution of this source may be constrained by nickel partitioning experiments at the pressures of the core–mantle boundary

Reductions in co-contraction following neuromuscular re-education in people with knee osteoarthritis

Background Both increased knee muscle co-contraction and alterations in central pain processing have been suggested to play a role in knee osteoarthritis pain. However, current interventions do not target either of these mechanisms. The Alexander Technique provides neuromuscular re-education and may also influence anticipation of pain. This study therefore sought to investigate the potential clinical effectiveness of the AT intervention in the management of knee osteoarthritis and also to identify a possible mechanism of action. Methods A cohort of 21 participants with confirmed knee osteoarthritis were given 20 lessons of instruction in the Alexander Technique. In addition to clinical outcomes EMG data, quantifying knee muscle co-contraction and EEG data, characterising brain activity during anticipation of pain, were collected. All data were compared between baseline and post-intervention time points with a further 15-month clinical follow up. In addition, biomechanical data were collected from a healthy control group and compared with the data from the osteoarthritis subjects. Results: Following AT instruction the mean WOMAC pain score reduced by 56% from 9.6 to 4.2 (P<0.01) and this reduction was maintained at 15 month follow up. There was a clear decrease in medial co-contraction at the end of the intervention, towards the levels observed in the healthy control group, both during a pre-contact phase of gait (p<0.05) and during early stance (p<0.01). However, no changes in pain-anticipatory brain activity were observed. Interestingly, decreases in WOMAC pain were associated with reductions in medial co-contraction during the pre-contact phase of gait. Conclusions: This is the first study to investigate the potential effectiveness of an intervention aimed at increasing awareness of muscle behaviour in the clinical management of knee osteoarthritis. These data suggest a complex relationship between muscle contraction, joint loading and pain and support the idea that excessive muscle co-contraction may be a maladaptive response in this patient group. Furthermore, these data provide evidence that, if the activation of certain muscles can be reduced during gait, this may lead to positive long-term clinical outcomes. This finding challenges clinical management models of knee osteoarthritis which focus primarily on muscle strengthening

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

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