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"McLean, Peter"
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Priest of lies
\"People are weak, and the poorer and more oppressed they are, the weaker they become--until they can't take it anymore. And when they rise up...may the gods help their oppressors. When Tomas Piety returned from the war, he just wanted to rebuild his empire of crime with his gang of Pious Men. But his past as a spy for the Queen's Men drew him back in and brought him more power than he ever imagined. Now, with half of his city in ashes and the Queen's Men at his back, the webs of political intrigue stretch out from the capital to pull Tomas in. Dannsburg is calling. In Dannsburg the nobility fight with words, not blades, but the results are every bit as bloody. In this pit of beasts, Tomas must decide once and for all whether he is truly the people's champion...or just a priest of lies\"-- Provided by publisher.
Book
Protein Equilibration Through Somatic Ring Canals in Drosophila
Although intercellular bridges resulting from incomplete cytokinesis were discovered in somatic Drosophila tissues decades ago, the impact of these structures on intercellular communication and tissue biology is largely unknown. In this work, we demonstrate that the ~250-nanometer-diameter somatic ring canals permit diffusion of cytoplasmic contents between connected cells and across mitotic clone boundaries and enable the equilibration of protein between transcriptionally mosaic follicle cells in the Drosophila ovary. We obtained similar, although more restricted, results in the larval imaginai discs. Our work illustrates the lack of cytoplasmic autonomy in these tissues and suggests a role for somatic ring canals in promoting homogeneous protein expression within the tissue.
Journal Article
Endosomal signaling of the receptor for calcitonin gene-related peptide mediates pain transmission
G protein-coupled receptors (GPCRs) are considered to function primarily at the plasma membrane, where they interact with extracellular ligands and couple to G proteins that transmit intracellular signals. Consequently, therapeutic drugs are designed to target GPCRs at the plasma membrane. Activated GPCRs undergo clathrin-dependent endocytosis. Whether GPCRs in endosomes control pathophysiological processes in vivo and are therapeutic targets remains uncertain. We investigated the contribution of endosomal signaling of the calcitonin receptor-like receptor (CLR) to pain transmission. Calcitonin gene-related peptide (CGRP) stimulated CLR endocytosis and activated protein kinase C (PKC) in the cytosol and extracellular signal regulated kinase (ERK) in the cytosol and nucleus. Inhibitors of clathrin and dynamin prevented CLR endocytosis and activation of cytosolic PKC and nuclear ERK, which derive from endosomal CLR. A cholestanol-conjugated antagonist, CGRP8–37, accumulated in CLR-containing endosomes and selectively inhibited CLR signaling in endosomes. CGRP caused sustained excitation of neurons in slices of rat spinal cord. Inhibitors of dynamin, ERK, and PKC suppressed persistent neuronal excitation. CGRP8–37–cholestanol, but not unconjugated CGRP8–37, prevented sustained neuronal excitation. When injected intrathecally to mice, CGRP8–37–cholestanol inhibited nociceptive responses to intraplantar injection of capsaicin, formalin, or complete Freund’s adjuvant more effectively than unconjugated CGRP8–37. Our results show that CLR signals from endosomes to control pain transmission and identify CLR in endosomes as a therapeutic target for pain. Thus, GPCRs function not only at the plasma membrane but also in endosomes to control complex processes in vivo. Endosomal GPCRs are a drug target that deserve further attention.
Journal Article
Reduction of Nitrite to Nitric Oxide during Ischemia Protects against Myocardial Ischemia-Reperfusion Damage
Nitric oxide ( NO·) is thought to protect against the damaging effects of myocardial ischemia-reperfusion injury, whereas xanthine oxidoreductase (XOR) normally causes damage through the generation of reactive oxygen species. In the heart, inorganic nitrite ( NO2-) has the potential to act as an endogenous store of NO·, liberated specifically during ischemia. Using a detection method that we developed, we report that under ischemic conditions both rat and human homogenized myocardium and the isolated perfused rat heart (Langendorff preparation) generate NO· from NO2- in a reaction that depends on XOR activity. Functional studies of rat hearts in the Langendorff apparatus showed that nitrite (10 and 100 μM) reduced infarct size from 47.3 ± 2.8% (mean percent of control ± SEM) to 17.9 ± 4.2% and 17.4 ± 1.0%, respectively (P < 0.001), and was associated with comparable improvements in recovery of left ventricular function. This protective effect was completely blocked by the NO· scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazole-1-oxyl 3-oxide (carboxy-PTIO). In summary, the generation of NO· from NO2-, by XOR, protects the myocardium from ischemia-reperfusion injury. Hence, if XOR is presented with NO2- as an alternative substrate, the resultant effects of its activity may be protective, by means of its production of NO·, rather than damaging.
Journal Article
Antiinflammatory Activity of Soluble Guanylate Cyclase: cGMP-Dependent Down-Regulation of P-Selectin Expression and Leukocyte Recruitment
Nitric oxide (NO) production by the vascular endothelium maintains an essential antiinflammatory, cytoprotective influence on the blood vessel wall. A key component of this activity is attributed to prevention of leukocyte-endothelial cell interactions, yet the underlying mechanisms remain unclear. The NO receptor, soluble guanylate cyclase (sGC), is expressed in endothelial cells but fulfils an unknown function. Therefore, we used intravital microscopy in mesenteric postcapillary venules from WT and endothelial nitric oxide synthase (eNOS) knockout (eNOS-/-) mice, and an sGC activator (BAY 41-2272), to investigate a potential role for sGC in the regulation of adhesion molecule expression and leukocyte recruitment. Leukocyte rolling and adhesion was 6-fold greater in eNOS-/-than WT animals. BAY 41-2272 and the NO-donor, diethylamine-NONOate, reduced leukocyte rolling and adhesion in eNOS-/-mice to levels observed in WT animals. These effects were blocked by the sGC inhibitor ODQ [1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one], which itself caused a 6-fold increase in leukocyte rolling and adhesion in WT mice. Increased leukocyte rolling and adhesion in IL-1β-treated mice was also inhibited by BAY 41-2272. Fluorescence-activated cell sorting analysis in vitro and a specific P-selectin neutralizing antibody in vivo revealed that selective down-regulation of P-selectin expression accounted for the anti-adhesive effects of sGC activation. These data demonstrate that sGC plays a key antiinflammatory role by inhibiting P-selectin expression and leukocyte recruitment.
Journal Article
Predictability of European winter 2021/2022: Influence of La Niña and stratospheric polar vortex
The Northern Hemisphere winter of 2021/2022 exhibited a positive North Atlantic Oscillation (NAO) which led to largely mild and wet conditions for Northern Europe. A moderate La Niña in the tropical Pacific and a stronger than average stratospheric polar vortex together explained the observed anomalies over the winter. Winter 2021/2022 was well predicted in general by seasonal forecast systems. The ensemble mean indicated a positive winter NAO and the forecast spread of forecasts from the Met Office GloSea6 seasonal prediction system spanned the observed mean sea level pressure anomaly for the whole winter and the individual months. However, December showed the largest departure from the mean of the forecast which is consistent with evidence from previous work that early winter ENSO teleconnections are too weak in model predictions. Nevertheless, around one in four members captured the negative NAO pattern in December. The strong pressure gradient and positive NAO predicted for the latter part of the winter allowed successful warning of the possibility of above average storminess and strong winds which occurred in February 2022. This is potentially useful information for the energy sector who increasingly rely on wind power and the insurance industry for warning of storm damage. The winter of 2021/2022 was mild over north‐west Europe and exhibited a positive North Atlantic Oscillation (NAO). The Met Office seasonal prediction system was able to capture this signal in the winter (DJF) ensemble mean driven by La Niña conditions in the tropical Pacific and a strong stratospheric polar vortex (SPV). The late winter was particularly stormy over north‐west Europe and the forecast was able to highlight February as the month where the risk of strong winds was greatest.
Journal Article
Predictability of European winter 2022/23
The boreal winter of 2022/23 was notable as a third consecutive winter in which La Niña had an influence on the European weather. The GloSea6 seasonal forecast system predicted a blocked circulation pattern in the North Atlantic in early winter (December), and then a transition through mid‐winter (January) into a more zonal pattern in late winter (February), consistent with the canonical La Niña teleconnection pattern seen previously. The seasonal forecast for the UK was an increased likelihood of near average temperatures, and drier‐ and calmer‐than‐average conditions. Both the predicted broad‐scale circulation patterns and UK winter mean weather conditions verified well against observations, and we show that seasonal forecasts of the North Atlantic Oscillation (NAO) over the last 10 winters show similar skill to previously reported hindcasts. Throughout the winter, the Madden–Julian Oscillation (MJO) was particularly active. On three occasions, it exhibited strong phases 6 and 7. There was also a sudden stratospheric warming (SSW) that occurred on 16th February. This was followed by colder conditions and associated impacts similar to the canonical negative NAO response over the UK, although the main impact fell in March and so did not affect the winter (December–January–February) mean conditions. The UK winter seasonal outlook for 2022/23 was an increased likelihood of near‐average temperatures, and an increased chance of drier‐ and calmer‐than‐average conditions, which verified well when compare with observations. The North Atlantic circulation pattern was predicted to be blocked (negative North Atlantic Oscillation) in December, and then a transition through January into a more zonal pattern in February (positive NAO), consistent with the expected teleconnection from the predicted La Niña conditions in the Pacific.
Journal Article
Predictability of European Winters 2017/2018 and 2018/2019: Contrasting influences from the Tropics and stratosphere
The European winters of 2017–18 and 2018–19 were not climatically extreme, but both winters had a major sudden stratospheric warming (SSW). In February 2018, an SSW led to an intense cold outbreak across Europe and further spells of cold weather in March. The SSW of January 2019, although well predicted and expected to increase the chance of a cold end to winter, apparently produced little impact. In this study, we examine the performance of the Met Office seasonal prediction system in these winters, and the influences that led to these outcomes. To achieve this latter objective, sets of numerical experiments are performed in which the tropical troposphere and the extratropical stratosphere are relaxed towards their observed state, allowing the influence of each on the North Atlantic‐European atmospheric circulation to be identified. Using these experiments, we show that the SSWs had similar impacts in each case, creating a signal of easterly surface wind anomalies in the weeks following the event. In contrast, tropical influences were opposite in the two winters, acting to strengthen the easterly signal at the end of February 2018 and opposing it in January 2019. The different apparent responses to the two events therefore came about largely through tropical tropospheric variability. Furthermore, we highlight the importance of a very strong cycle of the Madden‐Julian Oscillation (MJO) in late January and early February 2018 as an important driver for the February 2018 SSW. MJO teleconnections appear to have been critical in creating the large mid‐latitude wave 2 amplitude that has been identified as the immediate cause of this event. In February 2018, a strong negative North Atlantic Oscillation brought freezing weather to Europe following a sudden stratospheric warming (SSW). Yet the January 2019 SSW apparently had only a small impact. Here we explain these differences as the result of prevailing tropical influences—aiding cold weather in one case and inhibiting it in the other. Furthermore, we reveal a key role for the Madden‐Julian Oscillation in triggering the February 2018 SSW that led to European cold spell.
Journal Article
Prediction of European Winter 2023/24: Influence of a Strong El Niño
UK winter 2023/24 had a particularly stormy start, similar to 2015/16, another strong El Niño winter. Successfully predicted by the Met Office seasonal forecast system, this increased early‐winter storminess was associated with lower‐than‐average surface pressure to the west of the UK. Although late winter during El Niño is often associated with the negative phase of the North Atlantic Oscillation (NAO), in 2023/24 the NAO was near‐neutral in observations and weakly positive in the ensemble mean forecast, the late‐winter Atlantic surface pressure pattern in the forecast resembling the response observed during the very strongest El Niño events. Both observations and the forecast showed relatively higher pressure west of the UK, but north‐west Europe and the southern North Atlantic were more cyclonic than forecast. The forecast ensemble mean stratospheric polar vortex (SPV) was relatively strong, and unusually, the mean of ensemble members which had a sudden stratospheric warming (SSW) did not project strongly onto the negative NAO, analysis suggesting tropospheric teleconnections masked the usual SSW impact. Conversely, the observed SPV was weak; however, a mid‐January SSW had little surface impact. Overall, our analysis suggests that, despite some differences in late winter, El Niño was the principal driver of observed conditions in the North Atlantic‐European sector. The UK winter seasonal outlook for 2023/24 gave good guidance with increased chances of mild, wet and windy conditions, particularly in early winter, which verified well when compared with observations. December was particularly stormy. Our analysis suggests the key driver was the well forecast, strong El Niño event, with the late winter European teleconnection resembling past patterns of the very strongest events.
Journal Article