Global public policy, transnational policy communities, and their networks

Public policy has been a prisoner of the word "state." Yet, the state is reconfigured by globalization. Through "global public–private partnerships" and "transnational executive networks," new forms of authority are emerging through global and regional policy processes that coexist alongside nation-state policy processes. Accordingly, this article asks what is "global public policy"? The first part of the article identifies new public spaces where global policies occur. These spaces are multiple in character and variety and will be collectively referred to as the "global agora." The second section adapts the conventional policy cycle heuristic by conceptually stretching it to the global and regional levels to reveal the higher degree of pluralization of actors and multiple-authority structures than is the case at national levels. The third section asks: who is involved in the delivery of global public policy? The focus is on transnational policy communities. The global agora is a public space of policymaking and administration, although it is one where authority is more diffuse, decision making is dispersed and sovereignty muddled. Trapped by methodological nationalism and an intellectual agoraphobia of globalization, public policy scholars have yet to examine fully global policy processes and new managerial modes of transnational public administration

Crystal structure of rhodopsin bound to arrestin by femtosecond X-ray laser.

G-protein-coupled receptors (GPCRs) signal primarily through G proteins or arrestins. Arrestin binding to GPCRs blocks G protein interaction and redirects signalling to numerous G-protein-independent pathways. Here we report the crystal structure of a constitutively active form of human rhodopsin bound to a pre-activated form of the mouse visual arrestin, determined by serial femtosecond X-ray laser crystallography. Together with extensive biochemical and mutagenesis data, the structure reveals an overall architecture of the rhodopsin-arrestin assembly in which rhodopsin uses distinct structural elements, including transmembrane helix 7 and helix 8, to recruit arrestin. Correspondingly, arrestin adopts the pre-activated conformation, with a ∼20° rotation between the amino and carboxy domains, which opens up a cleft in arrestin to accommodate a short helix formed by the second intracellular loop of rhodopsin. This structure provides a basis for understanding GPCR-mediated arrestin-biased signalling and demonstrates the power of X-ray lasers for advancing the frontiers of structural biology

The extremely hot and dry 2018 summer in central and northern Europe from a multi-faceted weather and climate perspective

The summer of 2018 was an extraordinary season in climatological terms for northern and central Europe, bringing simultaneous, widespread, and concurrent heat and drought extremes in large parts of the continent with extensive impacts on agriculture, forests, water supply, and the socio-economic sector. Here, we present a comprehensive, multi-faceted analysis of the 2018 extreme summer in terms of heat and drought in central and northern Europe, with a particular focus on Germany. The heatwave first affected Scandinavia in mid-July and shifted towards central Europe in late July, while Iberia was primarily affected in early August. The atmospheric circulation was characterized by strongly positive blocking anomalies over Europe, in combination with a positive summer North Atlantic Oscillation and a double jet stream configuration before the initiation of the heatwave. In terms of possible precursors common to previous European heatwaves, the Eurasian double-jet structure and a tripolar sea surface temperature anomaly over the North Atlantic were already identified in spring. While in the early stages over Scandinavia the air masses at mid and upper levels were often of a remote, maritime origin, at later stages over Iberia the air masses primarily had a local-to-regional origin. The drought affected Germany the most, starting with warmer than average conditions in spring, associated with enhanced latent heat release that initiated a severe depletion of soil moisture. During summer, a continued precipitation deficit exacerbated the problem, leading to hydrological and agricultural drought. A probabilistic attribution assessment of the heatwave in Germany showed that such events of prolonged heat have become more likely due to anthropogenic global warming. Regarding future projections, an extreme summer such as that of 2018 is expected to occur every 2 out of 3 years in Europe in a +1.5 ∘C warmer world and virtually every single year in a +2 ∘C warmer world. With such large-scale and impactful extreme events becoming more frequent and intense under anthropogenic climate change, comprehensive and multi-faceted studies like the one presented here quantify the multitude of their effects and provide valuable information as a basis for adaptation and mitigation strategies

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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Targeting OGG1 arrests cancer cell proliferation by inducing replication stress

Altered oncogene expression in cancer cells causes loss of redox homeostasis resulting in oxidative DNA damage, e.g. 8-oxoguanine (8-oxoG), repaired by base excision repair (BER). PARP1 coordinates BER and relies on the upstream 8-oxoguanine-DNA glycosylase (OGG1) to recognise and excise 8-oxoG. Here we hypothesize that OGG1 may represent an attractive target to exploit reactive oxygen species (ROS) elevation in cancer. Although OGG1 depletion is well tolerated in non-transformed cells, we report here that OGG1 depletion obstructs A3 T-cell lymphoblastic acute leukemia growth in vitro and in vivo, validating OGG1 as a potential anti-cancer target. In line with this hypothesis, we show that OGG1 inhibitors (OGG1i) target a wide range of cancer cells, with a favourable therapeutic index compared to non-transformed cells. Mechanistically, OGG1i and shRNA depletion cause S-phase DNA damage, replication stress and proliferation arrest or cell death, representing a novel mechanistic approach to target cancer. This study adds OGG1 to the list of BER factors, e.g. PARP1, as potential targets for cancer treatment

Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.

BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden

Lake water analysis from the Kelbra barrier lake in Saxony-Anhalt during the Inland Water Remote Sensing Validation Campaign 2017

Inland Water Remote Sensing Validation Campaign 201

MTH1 as a target to alleviate T cell driven diseases by selective suppression of activated T cells

T cell-driven diseases account for considerable morbidity and disability globally and there is an urgent need for new targeted therapies. Both cancer cells and activated T cells have an altered redox balance, and up-regulate the DNA repair protein MTH1 that sanitizes the oxidized nucleotide pool to avoid DNA damage and cell death. Herein we suggest that the up-regulation of MTH1 in activated T cells correlates with their redox status, but occurs before the ROS levels increase, challenging the established conception of MTH1 increasing as a direct response to an increased ROS status. We also propose a heterogeneity in MTH1 levels among activated T cells, where a smaller subset of activated T cells does not upregulate MTH1 despite activation and proliferation. The study suggests that the vast majority of activated T cells have high MTH1 levels and are sensitive to the MTH1 inhibitor TH1579 (Karonudib) via induction of DNA damage and cell cycle arrest. TH1579 further drives the surviving cells to the MTH1[superscript low] phenotype with altered redox status. TH1579 does not affect resting T cells, as opposed to the established immunosuppressor Azathioprine, and no sensitivity among other major immune cell types regarding their function can be observed. Finally, we demonstrate a therapeutic effect in a murine model of experimental autoimmune encephalomyelitis. In conclusion, we show proof of concept of the existence of MTH1[superscript high] and MTH1[superscript low] activated T cells, and that MTH1 inhibition by TH1579 selectively suppresses pro-inflammatory activated T cells. Thus, MTH1 inhibition by TH1579 may serve as a novel treatment option against autoreactive T cells in autoimmune diseases, such as multiple sclerosis.EU/ERC H2020The European Research Council (TAROX Programme)Swedish Research CouncilEuropean CommissionAccepte