do Mass Spectrometry of Human Leukocyte Antigen Class I Peptidomes Reveals Strong Effects of Protein Abundance and Turnover on Antigen Presentation By feedproxy.google.com Published On :: 2015-03-01 Michal Bassani-SternbergMar 1, 2015; 14:658-673Research Full Article
do PaxDb, a Database of Protein Abundance Averages Across All Three Domains of Life By feedproxy.google.com Published On :: 2012-08-01 M. WangAug 1, 2012; 11:492-500Technological Innovation and Resources Full Article
do Quantitative Phosphoproteomics of Early Elicitor Signaling in Arabidopsis By feedproxy.google.com Published On :: 2007-07-01 Joris J. BenschopJul 1, 2007; 6:1198-1214Research Full Article
do {gamma}-Hydroxybutyrate does not mediate glucose inhibition of glucagon secretion [Signal Transduction] By feedproxy.google.com Published On :: 2020-04-17T00:06:05-07:00 Hypersecretion of glucagon from pancreatic α-cells strongly contributes to diabetic hyperglycemia. Moreover, failure of α-cells to increase glucagon secretion in response to falling blood glucose concentrations compromises the defense against hypoglycemia, a common complication in diabetes therapy. However, the mechanisms underlying glucose regulation of glucagon secretion are poorly understood and likely involve both α-cell–intrinsic and intraislet paracrine signaling. Among paracrine factors, glucose-stimulated release of the GABA metabolite γ-hydroxybutyric acid (GHB) from pancreatic β-cells might mediate glucose suppression of glucagon release via GHB receptors on α-cells. However, the direct effects of GHB on α-cell signaling and glucagon release have not been investigated. Here, we found that GHB (4–10 μm) lacked effects on the cytoplasmic concentrations of the secretion-regulating messengers Ca2+ and cAMP in mouse α-cells. Glucagon secretion from perifused mouse islets was also unaffected by GHB at both 1 and 7 mm glucose. The GHB receptor agonist 3-chloropropanoic acid and the antagonist NCS-382 had no effects on glucagon secretion and did not affect stimulation of secretion induced by a drop in glucose from 7 to 1 mm. Inhibition of endogenous GHB formation with the GABA transaminase inhibitor vigabatrin also failed to influence glucagon secretion at 1 mm glucose and did not prevent the suppressive effect of 7 mm glucose. In human islets, GHB tended to stimulate glucagon secretion at 1 mm glucose, an effect mimicked by 3-chloropropanoic acid. We conclude that GHB does not mediate the inhibitory effect of glucose on glucagon secretion. Full Article
do 12-LOX catalyzes the oxidation of 2-arachidonoyl-lysolipids in platelets generating eicosanoid-lysolipids that are attenuated by iPLA2{gamma} knockout [Signal Transduction] By feedproxy.google.com Published On :: 2020-04-17T00:06:05-07:00 The canonical pathway of eicosanoid production in most mammalian cells is initiated by phospholipase A2-mediated release of arachidonic acid, followed by its enzymatic oxidation resulting in a vast array of eicosanoid products. However, recent work has demonstrated that the major phospholipase in mitochondria, iPLA2γ (patatin-like phospholipase domain containing 8 (PNPLA8)), possesses sn-1 specificity, with polyunsaturated fatty acids at the sn-2 position generating polyunsaturated sn-2-acyl lysophospholipids. Through strategic chemical derivatization, chiral chromatographic separation, and multistage tandem MS, here we first demonstrate that human platelet-type 12-lipoxygenase (12-LOX) can directly catalyze the regioselective and stereospecific oxidation of 2-arachidonoyl-lysophosphatidylcholine (2-AA-LPC) and 2-arachidonoyl-lysophosphatidylethanolamine (2-AA-LPE). Next, we identified these two eicosanoid-lysophospholipids in murine myocardium and in isolated platelets. Moreover, we observed robust increases in 2-AA-LPC, 2-AA-LPE, and their downstream 12-LOX oxidation products, 12(S)-HETE-LPC and 12(S)-HETE-LPE, in calcium ionophore (A23187)-stimulated murine platelets. Mechanistically, genetic ablation of iPLA2γ markedly decreased the calcium-stimulated production of 2-AA-LPC, 2-AA-LPE, and 12-HETE-lysophospholipids in mouse platelets. Importantly, a potent and selective 12-LOX inhibitor, ML355, significantly inhibited the production of 12-HETE-LPC and 12-HETE-LPE in activated platelets. Furthermore, we found that aging is accompanied by significant changes in 12-HETE-LPC in murine serum that were also markedly attenuated by iPLA2γ genetic ablation. Collectively, these results identify previously unknown iPLA2γ-initiated signaling pathways mediated by direct 12-LOX oxidation of 2-AA-LPC and 2-AA-LPE. This oxidation generates previously unrecognized eicosanoid-lysophospholipids that may serve as biomarkers for age-related diseases and could potentially be used as targets in therapeutic interventions. Full Article
do G{alpha}q splice variants mediate phototransduction, rhodopsin synthesis, and retinal integrity in Drosophila [Signal Transduction] By feedproxy.google.com Published On :: 2020-04-24T06:08:45-07:00 Heterotrimeric G proteins mediate a variety of signaling processes by coupling G protein–coupled receptors to intracellular effector molecules. In Drosophila, the Gαq gene encodes several Gαq splice variants, with the Gαq1 isoform protein playing a major role in fly phototransduction. However, Gαq1 null mutant flies still exhibit a residual light response, indicating that other Gαq splice variants or additional Gq α subunits are involved in phototransduction. Here, we isolated a mutant fly with no detectable light responses, decreased rhodopsin (Rh) levels, and rapid retinal degeneration. Using electrophysiological and genetic studies, biochemical assays, immunoblotting, real-time RT-PCR, and EM analysis, we found that mutations in the Gαq gene disrupt light responses and demonstrate that the Gαq3 isoform protein is responsible for the residual light response in Gαq1 null mutants. Moreover, we report that Gαq3 mediates rhodopsin synthesis. Depletion of all Gαq splice variants led to rapid light-dependent retinal degeneration, due to the formation stable Rh1-arrestin 2 (Arr2) complexes. Our findings clarify essential roles of several different Gαq splice variants in phototransduction and retinal integrity in Drosophila and reveal that Gαq3 functions in rhodopsin synthesis. Full Article
do Biophysical characterization of SARAH domain-mediated multimerization of Hippo pathway complexes in Drosophila [Signal Transduction] By feedproxy.google.com Published On :: 2020-05-01T00:06:09-07:00 Hippo pathway signaling limits cell growth and proliferation and maintains the stem-cell niche. These cellular events result from the coordinated activity of a core kinase cassette that is regulated, in part, by interactions involving Hippo, Salvador, and dRassF. These interactions are mediated by a conserved coiled-coil domain, termed SARAH, in each of these proteins. SARAH domain–mediated homodimerization of Hippo kinase leads to autophosphorylation and activation. Paradoxically, SARAH domain–mediated heterodimerization between Hippo and Salvador enhances Hippo kinase activity in cells, whereas complex formation with dRassF inhibits it. To better understand the mechanism by which each complex distinctly modulates Hippo kinase and pathway activity, here we biophysically characterized the entire suite of SARAH domain–mediated complexes. We purified the three SARAH domains from Drosophila melanogaster and performed an unbiased pulldown assay to identify all possible interactions, revealing that isolated SARAH domains are sufficient to recapitulate the cellular assemblies and that Hippo is a universal binding partner. Additionally, we found that the Salvador SARAH domain homodimerizes and demonstrate that this interaction is conserved in Salvador's mammalian homolog. Using native MS, we show that each of these complexes is dimeric in solution. We also measured the stability of each SARAH domain complex, finding that despite similarities at both the sequence and structural levels, SARAH domain complexes differ in stability. The identity, stoichiometry, and stability of these interactions characterized here comprehensively reveal the nature of SARAH domain–mediated complex formation and provide mechanistic insights into how SARAH domain–mediated interactions influence Hippo pathway activity. Full Article
do Poland’s Elections: Domestic and Foreign Policy Implications By feedproxy.google.com Published On :: Wed, 18 Sep 2019 11:30:01 +0000 Research Event 30 September 2019 - 12:30pm to 1:30pm Chatham House | 10 St James's Square | London | SW1Y 4LE Event participants Dr Sławomir Dębski, Director, Polish Institute of International AffairsDr Stanley Bill, Senior Lecturer in Polish Studies, University of Cambridge On 13 October 2019, Poland goes to the polls in national elections. On the back of a strong performance in the European elections, the incumbent Law and Justice Party (PiS) is seeking to retain its absolute majority. The election takes place against a background of continued strong economic growth but amid disputes over the direction of social policy and a domestic contest about liberal values. The European Commission and the Polish government have clashed over reforms that the Commission believes could compromise the independence of the judiciary in the Poland. Meanwhile, in foreign policy terms, Poland has sought to develop good working relations with the Trump administration and supported a tough line towards Russia.The speakers will address the domestic and international significance of the Polish election. Will PiS be able to secure another majority? What would be the implications for the direction of social and political reform in Poland? And how could the elections shift Poland’s approach to politics at the European level and its wider foreign policy? Event attributes Chatham House Rule Department/project Europe Programme Alina Lyadova Europe Programme Coordinator Email Full Article
do Britain, the EU and the Power of Myths: What Does Brexit Reveal about Europe? By feedproxy.google.com Published On :: Thu, 31 Oct 2019 15:10:01 +0000 Invitation Only Research Event 14 November 2019 - 8:30am to 9:30am Chatham House | 10 St James's Square | London | SW1Y 4LE Event participants Kalypso Nicolaïdis, Professor of International Relations, Faculty Fellow, St Antony’s College, University of Oxford; Author, Exodus, Reckoning, Sacrifice: Three Meanings of BrexitChair: Hans Kundnani, Senior Research Fellow, Europe Programme, Chatham House When we look back on Brexit, what will it tell us about Europe? Will it simply be that an insular UK was always different and destined to never fit in? Will it be that the UK's decision to leave revealed deeper problems with the EU? Or will it be that the threat created by the UK's withdrawal united the continent and saved the European project?The speaker will explore Brexit through the prism of biblical and ancient Greek mythology. She will examine the reasons behind Britain’s decision to leave the EU and imagine a ‘better Europe’ that has learnt the lessons of the past and reconciled the divisions exposed by the Brexit vote. How can the EU reinvent itself and re-engage its citizens? And where does a post-Brexit UK fit?Attendance at this event is by invitation only. Event attributes Chatham House Rule Department/project Europe Programme, Britain and Europe: The Post-Referendum Agenda Alina Lyadova Europe Programme Coordinator Email Full Article
do Don’t Be Afraid of Political Fragmentation By feedproxy.google.com Published On :: Mon, 16 Dec 2019 11:00:17 +0000 16 December 2019 Pepijn Bergsen Research Fellow, Europe Programme @pbergsen LinkedIn If managed correctly, splintering and more volatile political systems – so-called ‘Dutchification’ – need not be a ticket to political and policy paralysis. 2019-12-16-Dutch-Election.jpg Voters cast their vote as part of the Dutch general elections on March 15, 2017 at a polling station in a mill in Oisterwijk. Photo by ROB ENGELAAR/AFP via Getty Images. In recent decades, political party systems across Europe have fragmented and electoral volatility has increased. The number of parties represented in parliaments across the continent has grown and the formerly dominant mainstream parties have seen their support base collapse, forcing parties into often uncomfortable and unstable coalitions.From the United Kingdom to Germany, politicians and commentators talk of such scenarios in often apocalyptic terms and associate it with political instability and policy paralysis.They shouldn’t. Instead they should focus their energy on making these increasingly competitive political markets work.The Netherlands is frequently held up as a prime example of this process, which is therefore sometimes referred to as ‘Dutchification’. Its highly proportional political system has created the opportunity for new parties and specific interest groups to win parliamentary representation, ranging from an animal rights party and a party catering specifically to the interests of the elderly.This has been accompanied by increased electoral volatility. In the 1970s, less than 15% of seats in the Dutch parliament would change party at any election, but in the last election in 2017, this was just over a quarter. The system also created space for the relatively early rise of populist far-right parties, though it was not the cause of their rise.Nevertheless, despite the regularly difficult coalition politics, it remains one of the most well-governed countries in the world.A short history of fragmentationLooking at the effective number of parties represented in parliaments, the number of parties, corrected for their size, provides a good measure of the extent of fragmentation. In the Netherlands this steadily increased from around four in the 1980s to over eight following the election in 2017. Even the populist far-right vote has fragmented, with two parties partly competing for the same electorate. In other countries it has been a more recent phenomenon. Spain remained a de facto two-party system until the financial crisis. Dissatisfaction with both mainstream parties has seen challenger parties on both the left and the right attract significant support, making it harder to form stable coalitions. Political fragmentation decreased slightly in Italy in recent years, but that was from a high base as it shot up in the early 1990s when the post-war political settlement crumbled.German politics, long a hallmark of stability, is struggling with the decrease in support for the parties that dominated its political scene in the post-war period. The Christian Democrats and Social Democrats only barely managed to win a majority together in the election in 2017, at 53.4% of the vote compared with the 81.3% achieved 30 years earlier. The latest polls suggest they would only get to 40% together if an election were held today.A similar trend is visible within the European Parliament. Whereas the two largest groups in the European Parliament, the Christian Democrats and the Social Democrats, together won 66% of the vote in the election in 1999, they did not even manage to win a majority together in 2019, taking just 39.5% of the vote.No crisis of democracyIf electoral volatility and political fragmentation does indeed constitute some sort of crisis of democracy, we should expect to see voters become unhappy about how their national democracy functions. Largely, the opposite seems to be the case.In the Netherlands, satisfaction with its democracy went up at the same time as Dutchification did its work. Similar trends are visible in other highly fragmented European political systems, often those with very proportional systems. Despite regular minority governments, satisfaction with democracy is above 90% in Denmark and at 80% in Sweden, according to the latest Eurobarometer data.In comparison, it stood at 52% in the United Kingdom and 53% in France, where the electoral system has, at least on the surface, prevented the kind of fragmentation supposedly plaguing proportional systems.Satisfaction with democracy seems to be affected by a number of factors. This includes the state of the economy, particularly in countries that were hit the hardest by the global financial and euro zone crises. Nevertheless, the data suggests that, even if we can’t say that Dutchification by definition leads to more satisfaction with democracy, it is clearly not associated with falling faith in the system.A competitive political marketDutchification should be seen as accompanying a more competitive political marketplace. A more emancipated, demanding and politically engaged electorate than in the post-war decades is willing to shop around instead of merely vote according to socioeconomic class or other dividing lines, such as religious ones. The fragmented parliaments that emerge as a result provide better representation of different groups within European societies.This makes life harder for Europe’s political parties and politicians, as they juggle large coalitions, or changing coalitions under minority governments, but provides voters with more choice and democratic renewal. If handled correctly this would also allow more responsiveness to shifts in public opinion.Such democratic creative destruction in competitive political markets is to be celebrated in a well-functioning democracy. Just as companies prefer to operate in an oligopoly, political parties prefer the stability of limited political competition. But wishing for this kind of stability comes perilously close to preferring stability over proper representation.Worrying about Dutchification risks confusing a crisis of the traditional mainstream parties with a crisis of democracy. For some countries, particularly those like the Netherlands and Denmark which have longer histories of consensus-based politics and coalition building, this is an easier adjustment. But this should not be an excuse to not attempt to make politics work better as they were forced to go through, arguably still ongoing, adjustment processes too.Instead of investing in futile attempts to get back to how things were in the old days, or hoping this will somehow magically happen, political leaders and parties across Europe need to reassess how they deal with the new reality of Dutchification. Full Article
do Another CDU Leadership Race Begins in Merkel’s Shadow By feedproxy.google.com Published On :: Fri, 28 Feb 2020 13:59:32 +0000 28 February 2020 Quentin Peel Associate Fellow, Europe Programme @QuentinPeel The election of a new leader of the chancellor’s party will be another contest over her legacy. 2020-02-28-Merkel.jpg German Chancellor Angela Merkel is depicted on a float in the Rosenmontag parade in Mainz on 24 February. Photo: Getty Images. Perhaps it will be second time lucky. At the end of April, Germany’s Christian Democratic Union (CDU) will elect a new party leader to follow in the footsteps of Angela Merkel. An emergency party congress has been summoned to do that after the surprise resignation of Annegret Kramp-Karrenbauer, Merkel’s chosen successor.The plan is to leave the decision on who will be the CDU candidate for chancellor at the next election until after Germany’s EU presidency concludes in December. So Merkel will keep her job until 2021, and the new leader will have to learn to live with her.The three leading candidates are Armin Laschet, Friedrich Merz and Norbert Röttgen, all from the state of North Rhine-Westphalia. Two of the three – Merz and Röttgen – were sacked by Merkel from their former jobs. They have not forgotten. Only Armin Laschet, currently CDU leader in North Rhine-Westphalia and state premier, can be described as a Merkel loyalist, true to her centrist mantra.He is the man to beat, having teamed up with Jens Spahn, the 39-year-old health minister, who is popular with party conservatives. Spahn will run as his deputy, so the team straddles the left-right divide in the party. But the contest still seems set to be a bitter battle between pro- and anti-Merkel factions that could leave the party badly split.After nearly 15 years as chancellor, and 18 years as CDU leader, Merkel remains the most popular politician in Germany. In spite of criticism that she lacks vision, her caution and predictability appear to be just what most German voters like.But her term in office has also seen the steady shrinking of the centre ground in German politics, with the rise of the environmentalist Green party and the far-right Alternative for Germany (AfD) at the expense of the centre-right CDU and the centre-left Social Democratic Party (SPD).The battle for the soul of the CDU is between those who think Merkel has been too left-wing, and want a more conservative leader to win back AfD voters, and those who believe that the CDU must stay in the centre, and prepare for a future coalition with the Greens. Merz is seen as the former, Laschet and Röttgen the latter.Unless Laschet emerges as the clear winner in April, the leadership contest is likely to leave Germany sorely distracted by domestic politics just as it takes over the EU presidency in the second half of the year. Instead of Merkel having a triumphant international swansong on the EU stage, she could be battling to protect her inheritance at home.The one area on which all three leadership candidates seem to agree is foreign policy: they all want Germany to take more leadership and responsibility, and for the European Union to play a bigger role in security, defence and international affairs. They are all Atlanticists, but critical of Donald Trump’s ‘America First’ stance. All are on the record criticizing the chancellor – at least tacitly – for not having a more vigorous foreign policy.There the similarity ends.On the right, the 64-year-old Merz is both the most conservative and the most popular with the party grassroots. He fell out with the chancellor when she took over his job as CDU leader in parliament in 2002. He quit politics to become a corporate lawyer (and a millionaire), but never lost his political ambition. He is an economic liberal but socially conservative, a strong critic of Merkel’s migration policy and her lack of clear leadership. Critics say he is a man of the past, and not a team player.On the EU, he believes Germany is ‘leaving too much to the French’. If France and Germany cannot agree on financial matters, he said at the London School of Economics in February, they should instead forge a stronger EU industrial policy focused on creating more ‘European champions’.Laschet, the Merkel loyalist, is four years younger, and from the left of the party. Like Merz, he is a former member of the European parliament. In 2015, he defended Merkel’s open border policy to accept refugees stranded in the Balkans. On Russia, however, he is more critical, calling for a new effort to re-engage with Vladimir Putin. Most recently, at the Munich Security Conference, he called for stronger Franco-German relations, and more support for the eurozone reforms proposed by Emmanuel Macron.As CDU leader in North Rhine-Westphalia, Laschet has the strongest power base. He earned his political spurs there by winning the last state election in 2017, in contrast to Röttgen, who lost to the SPD and Greens five years earlier.Röttgen, chairman of the Bundestag foreign affairs committee, is the surprise candidate. Once a Merkel favourite, they fell out when she sacked him as environment minister after he lost the North Rhine-Westphalia election. By throwing his hat in the ring, he has forced it to become an open contest. He is independent-minded and outspoken, but not as bitterly hostile to the chancellor as Merz, so he could be a compromise candidate.Laschet is clearly the man Merkel would find it easiest to live with. The decision will be taken by a party congress, not a grassroots ballot, which gives him a better chance. But Merz is the most eloquent orator and seen as the best campaigner. The challenge for party members is whether they believe it is better to swing right and squeeze the AfD, or stick to the centre to hold onto voters tempted by the Greens, who have replaced the SPD as the second-most popular party in Germany.The race is wide open. So is the future of the CDU. The only prediction one can make with much certainty is that as long as Merkel remains chancellor, any successor will struggle to get out of her shadow. Full Article
do Processivity of dextransucrases synthesizing very-high-molar-mass dextran is mediated by sugar-binding pockets in domain V [Glycobiology and Extracellular Matrices] By feedproxy.google.com Published On :: 2020-04-24T06:08:45-07:00 The dextransucrase DSR-OK from the Gram-positive bacterium Oenococcus kitaharae DSM17330 produces a dextran of the highest molar mass reported to date (∼109 g/mol). In this study, we selected a recombinant form, DSR-OKΔ1, to identify molecular determinants involved in the sugar polymerization mechanism and that confer its ability to produce a very-high-molar-mass polymer. In domain V of DSR-OK, we identified seven putative sugar-binding pockets characteristic of glycoside hydrolase 70 (GH70) glucansucrases that are known to be involved in glucan binding. We investigated their role in polymer synthesis through several approaches, including monitoring of dextran synthesis, affinity assays, sugar binding pocket deletions, site-directed mutagenesis, and construction of chimeric enzymes. Substitution of only two stacking aromatic residues in two consecutive sugar-binding pockets (variant DSR-OKΔ1-Y1162A-F1228A) induced quasi-complete loss of very-high-molar-mass dextran synthesis, resulting in production of only 10–13 kg/mol polymers. Moreover, the double mutation completely switched the semiprocessive mode of DSR-OKΔ1 toward a distributive one, highlighting the strong influence of these pockets on enzyme processivity. Finally, the position of each pocket relative to the active site also appeared to be important for polymer elongation. We propose that sugar-binding pockets spatially closer to the catalytic domain play a major role in the control of processivity. A deep structural characterization, if possible with large-molar-mass sugar ligands, would allow confirming this hypothesis. Full Article
do It takes two (Las1 HEPN endoribonuclease domains) to cut RNA correctly [RNA] By feedproxy.google.com Published On :: 2020-05-01T00:06:09-07:00 The ribosome biogenesis factor Las1 is an essential endoribonuclease that is well-conserved across eukaryotes and a newly established member of the higher eukaryotes and prokaryotes nucleotide-binding (HEPN) domain-containing nuclease family. HEPN nucleases participate in diverse RNA cleavage pathways and share a short HEPN nuclease motif (RφXXXH) important for RNA cleavage. Most HEPN nucleases participate in stress-activated RNA cleavage pathways; Las1 plays a fundamental role in processing pre-rRNA. Underscoring the significance of Las1 function in the cell, mutations in the human LAS1L (LAS1-like) gene have been associated with neurological dysfunction. Two juxtaposed HEPN nuclease motifs create Las1's composite nuclease active site, but the roles of the individual HEPN motif residues are poorly defined. Here using a combination of in vivo experiments in Saccharomyces cerevisiae and in vitro assays, we show that both HEPN nuclease motifs are required for Las1 nuclease activity and fidelity. Through in-depth sequence analysis and systematic mutagenesis, we determined the consensus HEPN motif in the Las1 subfamily and uncovered its canonical and specialized elements. Using reconstituted Las1 HEPN-HEPN' chimeras, we defined the molecular requirements for RNA cleavage. Intriguingly, both copies of the Las1 HEPN motif were important for nuclease function, revealing that both HEPN motifs participate in coordinating the RNA within the Las1 active site. We also established that conformational flexibility of the two HEPN domains is important for proper nuclease function. The results of our work reveal critical information about how dual HEPN domains come together to drive Las1-mediated RNA cleavage. Full Article
do Thioredoxin regulates human mercaptopyruvate sulfurtransferase at physiologically-relevant concentrations [Enzymology] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 3-Mercaptopyruvate sulfur transferase (MPST) catalyzes the desulfuration of 3-mercaptopyruvate (3-MP) and transfers sulfane sulfur from an enzyme-bound persulfide intermediate to thiophilic acceptors such as thioredoxin and cysteine. Hydrogen sulfide (H2S), a signaling molecule implicated in many physiological processes, can be released from the persulfide product of the MPST reaction. Two splice variants of MPST, differing by 20 amino acids at the N terminus, give rise to the cytosolic MPST1 and mitochondrial MPST2 isoforms. Here, we characterized the poorly-studied MPST1 variant and demonstrated that substitutions in its Ser–His–Asp triad, proposed to serve a general acid–base role, minimally affect catalytic activity. We estimated the 3-MP concentration in murine liver, kidney, and brain tissues, finding that it ranges from 0.4 μmol·kg−1 in brain to 1.4 μmol·kg−1 in kidney. We also show that N-acetylcysteine, a widely-used antioxidant, is a poor substrate for MPST and is unlikely to function as a thiophilic acceptor. Thioredoxin exhibits substrate inhibition, increasing the KM for 3-MP ∼15-fold compared with other sulfur acceptors. Kinetic simulations at physiologically-relevant substrate concentrations predicted that the proportion of sulfur transfer to thioredoxin increases ∼3.5-fold as its concentration decreases from 10 to 1 μm, whereas the total MPST reaction rate increases ∼7-fold. The simulations also predicted that cysteine is a quantitatively-significant sulfane sulfur acceptor, revealing MPST's potential to generate low-molecular-weight persulfides. We conclude that the MPST1 and MPST2 isoforms are kinetically indistinguishable and that thioredoxin modulates the MPST-catalyzed reaction in a physiologically-relevant concentration range. Full Article
do The recalibration of Chinese assertiveness: China's responses to the Indo-Pacific challenge By feedproxy.google.com Published On :: Wed, 08 Jan 2020 11:14:26 +0000 8 January 2020 , Volume 96, Number 1 Read online Feng Liu In response to the changing geopolitical landscape in Asia, both China and the United States attempt to alter the regional order in their own favour, both in the economic and security realms. This article shows how diverging views on future arrangements are leading to strategic shifts and increasing tension between these two Great Powers. As part of its quest for Great-Power status, China has been actively pushing its regional initiatives such as the Belt and Road Initiative (BRI) and the Asian Infrastructure Investment Bank (AIIB), as well as adopting assertive security policies towards its neighbours. In contrast, in order to counter China's growing influence America's regional strategy is undergoing a subtle shift from ‘rebalancing to Asia’ to focusing on the ‘Indo-Pacific’ region. However, amid an intensifying trade war and other challenges facing the region, China has chosen to moderate its proactive foreign policy-orientation in the past few years. In particular, China has made attempts to downplay its domestic rhetoric, rebuild strategic relationship with India and Japan, and to reassure ASEAN states in the South China Sea. In response to the Indo-Pacific strategy, it would be more effective for China to articulate a more inclusive regional vision and promote an institutional framework that also accommodates a US presence in the region. Full Article
do Non-traditional security cooperation between China and south-east Asia: implications for Indo-Pacific geopolitics By feedproxy.google.com Published On :: Wed, 08 Jan 2020 11:17:30 +0000 8 January 2020 , Volume 96, Number 1 Read online Xue Gong The ‘free and open Indo-Pacific’ (FOIP) strategy, actively promoted by the United States with support from its allies and partners, is a significant geopolitical response to China's growing power and expanding influence in Asia and beyond. Beijing has adopted various new strategies to cope with the challenges related to FOIP. One of these strategies is to secure a robust relationship with south-east Asia in order to make these regional states either neutral to or less supportive of the Indo-Pacific vision. In addition to economic statecraft and soft power, Beijing believes that it can also tap into the domain of non-traditional security (NTS) to strengthen relations with this region to position itself better in the intensifying regional geopolitical competition. The article addresses the following question: what is the impact of China's NTS cooperation with south-east Asia on Beijing's geopolitical rivalry with other major powers in the Indo-Pacific region? The article argues that China's NTS cooperation with south-east Asian countries may help China maintain its geopolitical standing in the region, but it is unlikely to lead to any dramatic increase of China's strategic influence in the region. This essentially means that Beijing may be able to prevent ASEAN or most ASEAN member states from lending substantive and strong support to the Indo-Pacific construct, but it will not be able to stop ASEAN states from supporting some elements of the FOIP. Full Article
do Japan's ‘Indo-Pacific’ question: countering China or shaping a new regional order? By feedproxy.google.com Published On :: Wed, 08 Jan 2020 11:19:14 +0000 8 January 2020 , Volume 96, Number 1 Read online Kei Koga Japan's primary objective of the ‘free and open Indo-Pacific’ (FOIP) strategy is to shape and consolidate regional order in the Indo-Pacific region based on the existing rules-based international order. The concept initially aimed to achieve two different objectives—shaping a regional order in the Indo-Pacific and ensuring the defence of Japan; however, Japan has gradually shifted its strategic focus onto the former, separating national defence from the FOIP concept, which reflects a change in the degree of its commitment to the two objectives. On the one hand, as its overall security strategy, Japan has determined to steadily enhance its national defence by increasing its own defence capabilities and strengthening the US–Japan alliance, while transforming its partnerships with like-minded states, such as Australia and India, into a diplomatic, and potentially military, alignment. This has been brought about by shifts in the regional balance of power, particularly the rise of China and the relative decline of the United States. On the other hand, as part of its FOIP strategy, Japan's attempts to build a new regional order in the Indo-Pacific region aim to defend the existing rules-based order established by the United States from challengers, particularly China. Yet, given the strategic uncertainty over Japan's international coalition-building efforts to create a new regional order, Japan has made its approach flexible; Tokyo is using its ambiguous FOIP concept to gauge other states' responses, understand their perspectives, and change its strategic emphases accordingly—so-called ‘tactical hedging’. Japan has pursued similar means to achieve the two key objectives. Nevertheless, the country's core interest, the defence of Japan, is more imperative than building a regional order in the Indo-Pacific region, and Japan faces different types of challenges in the future. Full Article
do Evasive balancing: India's unviable Indo-Pacific strategy By feedproxy.google.com Published On :: Wed, 08 Jan 2020 11:37:22 +0000 8 January 2020 , Volume 96, Number 1 Read online Rajesh Rajagopalan India has adopted the Indo-Pacific concept with uncharacteristic speed. This article examines India's Indo-Pacific strategy, which evolved out of its earlier ‘Look East’ and ‘Act East’ policies but is much more focused on strategic concerns than on trade or connectivity. As such, the strategy is subset of its China policy, and includes contradictory elements of balancing China by building partnerships with the United States as well as with regional powers, while simultaneously pursuing a reassurance strategy to convince Beijing that India is not really balancing China. The combination of these contradictory elements is characterized as evasive balancing, which is a more useful concept than either pure balancing or hedging for understanding the policies of India and of many other countries in the region that are trying to manage China's rise. However, reassurance strategies rarely work and the combination of balancing and reassurance is even less likely to be viable. Full Article
do Is Australia's Indo-Pacific strategy an illusion? By feedproxy.google.com Published On :: Wed, 08 Jan 2020 11:39:40 +0000 8 January 2020 , Volume 96, Number 1 Read online Brendan Taylor Australia has been among the most prominent advocates of the increasingly popular Indo-Pacific concept. This article argues that Canberra's enthusiasm for the concept stems from its appeal to the two dominant traditions of Australian foreign policy—a ‘dependent ally’ tradition and a ‘middle power’ approach. While these two traditions are typically seen as being in tension, the Indo-Pacific concept provides a rare point of convergence between them. The article begins by outlining the appeal of the Indo-Pacific concept to each of these traditions. Using a case-study of recent Australian policy toward the South China Sea disputes, however, the article then demonstrates that Australia has in practice implemented its stated Indo-Pacific strategy far less consistently than its very vocal support would appear to suggest. This disjuncture is attributed to the growing influence of a third, generally understudied, ‘pragmatic’ Australian foreign policy tradition. Because Australia has been such a prominent champion of the Indo-Pacific concept, the article concludes that this divergence between the rhetoric and the reality of Australia's Indo-Pacific strategy threatens to have a negative impact on the concept's broader international appeal and sustainability, particularly among Australia's south-east Asian neighbours. Full Article
do Indonesia and the ASEAN outlook on the Indo-Pacific By feedproxy.google.com Published On :: Wed, 08 Jan 2020 11:44:49 +0000 8 January 2020 , Volume 96, Number 1 Read online Dewi Fortuna Anwar Indonesia has taken a leadership role within the Association of Southeast Asian Nations (ASEAN) in drafting a common outlook on the Indo-Pacific concept. The widening of Indonesia's geostrategic canvas from the Asia–Pacific to the Indo-Pacific is in line with President Joko Widodo's intent to make Indonesia a Global Maritime Fulcrum (GMF). In view of the rivalry between the US and China and the emergence of various Indo-Pacific initiatives from other countries, Indonesia believes that ASEAN must try to maintain its centrality. The draft of Indonesia's perspective for an ASEAN outlook on the Indo-Pacific: towards a peaceful, prosperous, and inclusive region was submitted for considerations by ASEAN, and after 18 months of intensive lobbying by Indonesia the concept was finally adopted at the ASEAN Summit in June 2019. The ASEAN outlook promotes the principles of openness, inclusiveness, transparency, respect for international law and ASEAN centrality in the Indo-Pacific region. It proposes a building-block approach, seeking commonalities between existing regional initiatives in which ASEAN-led mechanisms will act as a fulcrum for both norm-setting and concrete cooperation. Rather than creating a new regional architecture, the East Asia Summit (EAS) is proposed as the platform for advancing the Indo-Pacific discourse and cooperation. Indonesia's ASEAN outlook on the Indo-Pacific marks its renewed foreign policy activism as a middle power and underlines the continuing importance that Indonesia places on ASEAN as the cornerstone of its foreign policy, emphasising ASEAN's centrality as the primary vehicle for managing relations with the major powers in the Indo-Pacific region. Full Article
do Consigned to hedge: south-east Asia and America's ‘free and open Indo-Pacific’ strategy By feedproxy.google.com Published On :: Wed, 08 Jan 2020 11:47:11 +0000 8 January 2020 , Volume 96, Number 1 Read online See Seng Tan This article assesses how south-east Asian countries and the Association of Southeast Asian Nations (ASEAN) have responded to the ‘free and open Indo-Pacific’ (FOIP) strategies promoted by the United States and the other countries in the Quadrilateral Security Dialogue (the ‘Quad’: US, Japan, Australia and India). Their nuanced ripostes imply a persistent commitment to hedging and shifting limited alignments in the face of growing great rivalry and the lack of a clear FOIP vision among Quad members. In the face of external pressure to take sides, the ASEAN states are likely to keep hedging through working selectively with China and the United States. Given the United States' apparent preference to balance China and Trump's disregard for multilateralism, ASEAN's ability to maintain its centrality in the evolving regional architecture is in doubt—despite the Quad countries' (belated) accommodation of ASEAN in their FOIP strategies. However, the success of the US strategy depends on Washington's ability to build and sustain the requisite coalition to balance Beijing. ASEAN has undertaken efforts to enhance bilateral security collaboration with China and the United States respectively. In doing so, ASEAN is arguably seeking to informally redefine its centrality in an era of Great Power discord and its ramifications for multilateralism. Full Article
do The institutionalization of the Indo-Pacific: problems and prospects By feedproxy.google.com Published On :: Wed, 08 Jan 2020 11:49:12 +0000 8 January 2020 , Volume 96, Number 1 Read online Kai He and Huiyun Feng Although the term ‘Indo-Pacific’ has become popular in the foreign policy discourse of some countries, we have yet to see any significant institution-building in the Indo-Pacific region. Borrowing insights from functional institutionalism and political leadership studies of international regimes, we introduce a ‘leadership–institution’ model to explore the problems and prospects of institutionalizing the Indo-Pacific. Through a comparative case study of the institutionalization of the Asia–Pacific vs the Indo-Pacific, we argue that two crucial factors contributed to the slow institutionalization of the Indo-Pacific as a regional system in world politics: the lack of ideational leadership from an epistemic community and the weak executive leadership from a powerful state. While ideational leaders can help states identify and expand common interests in cooperation, executive leadership will facilitate states to overcome operational obstacles in cooperation, such as the ‘collective action’ problem and the ‘relative gains’ concern. The future of institution-building in the Indo-Pacific will depend on whether and how these two leadership roles are played by scholars and states in the region. In the conclusion, we discuss the challenges of institutionalizing the Indo-Pacific and highlight China as a wild card in the future of Indo-Pacific regionalism. Full Article
do The Belt and Road Initiative: geo-economics and Indo-Pacific security competition By feedproxy.google.com Published On :: Wed, 08 Jan 2020 11:58:35 +0000 8 January 2020 , Volume 96, Number 1 Read online Mingjiang Li The Belt and Road Initiative (BRI) has been regarded by international society as a major policy tool in China's geo-economic strategy. Under this policy platform, Beijing has pledged to invest billions of dollars in the infrastructure and industrial sectors across Eurasia and in the Indo-Pacific nations. It is widely believed that such huge amount of investment will inevitably generate significant geostrategic repercussions in these regions. In response to the BRI, the United States and other powers have come up with a ‘free and open Indo-Pacific’ strategy. This article attempts to address the following question: what impact is the BRI likely to have on the security ties between China and the other major players in the Indo-Pacific? The author finds that the BRI may significantly transform China's international security policy and the expansion of Beijing's security influence may further intensify the security competition between China and other major powers in the Indo-Pacific region. The article also proposes a new analytical angle for the study of geo-economics that unpacks the role of economic activities and processes in generating geopolitical intentions and catalysing geopolitical competition. Full Article
do Developmental peace in east Asia and its implications for the Indo-Pacific By feedproxy.google.com Published On :: Wed, 08 Jan 2020 12:01:42 +0000 8 January 2020 , Volume 96, Number 1 Read online Ling Wei This article adopts a constructive approach to examining the problem of the Indo-Pacific construct. Through reflection on the east Asian experience, it proposes an analytical framework of developmental peace as a constellation of international practices, which means that the more economic development is prioritized by states in regional processes, the more likely it is that a sustainable peace will be achieved. States participating in regional integration comprise a community of practice. On the basis of a shared understanding that development is of overriding importance and underpins security and state legitimacy, the community takes economic development as the anchoring practice; this practice embodies and enacts constitutive rules and fundamental norms for a broader set of practices in regional processes, such as peaceful coexistence and non-interference. The more economic development is prioritized on domestic and regional agendas, the more likely it is that conflicts in the security realm will be relaxed or even resolved to protect security interests. The author draws some useful implications from the developmental peace in east Asia for the Indo-Pacific construct, among which the most important include building shared understandings on the prioritization of economic development, taking advantage of the Regional Comprehensive Economic Partnership (RCEP), Comprehensive and Progressive Agreement for Trans-Pacific Partnership (CPTPP) and the Asian Infrastructure Investment Bank, and using the code of conduct process as a vehicle and best practice to facilitate rule-making for the maritime order. Finally, the author briefly discusses the contributions of the study and limitations of the model. Full Article
do Understanding the dynamics of the Indo-Pacific: US–China strategic competition, regional actors, and beyond By feedproxy.google.com Published On :: Wed, 08 Jan 2020 21:20:01 +0000 6 November 2019 , Volume 96, Number 1 The first issue of International Affairs in 2020 explores the geopolitics of the 'Indo-Pacific' region. Read online Kai He and Mingjiang Li As a geographical concept, ‘Indo-Pacific’ has existed for decades. As a political and strategic concept, it has since 2010 gradually become established in the foreign policy lexicon of some countries, especially Australia, India, Japan and the United States. However, China seems to be reluctant to identify itself as part of the Indo-Pacific; Chinese leaders believe that the US-led Indo-Pacific strategy aims to contain China's rise. While the battle between the two geographical concepts ‘Indo-Pacific’ and ‘Asia–Pacific’ may be fairly easily settled in the future, US–China strategic competition has just begun. Will the Indo-Pacific become a battlefield for US–China rivalry? How will China cope with the US ‘free and open Indo-Pacific’ (FOIP) strategy? How will other regional actors respond to the US–China strategic competition in the Indo-Pacific? What are the strategic implications of the ‘Indo-Pacific’ concept for regional order transformation? How will the Indo-Pacific be institutionalized, economically, politically and strategically? This article introduces the January 2020 special issue of International Affairs, which aims to address those questions, using both country-specific and regional perspectives. Seven articles focus on the policy responses of major players (Australia, China, India, Indonesia, Japan and ASEAN) to the US FOIP strategy and related US–China rivalry in the region. A further three articles examine the profound implications of Indo-Pacific dynamics for regional institution-building and for geopolitical and geo-economic architecture. Full Article
do Webinar: Are the Gulf Standoffs Resolvable? By feedproxy.google.com Published On :: Wed, 15 Apr 2020 08:15:01 +0000 Research Event 21 April 2020 - 1:00pm to 2:00pm Event participants David Roberts, Assistant Professor and School of Security Studies Lead for Regional Security and Development, King's College LondonKristian Coates Ulrichsen, Associate Fellow, Middle East and North Africa Programme, Chatham HouseChair: Sanam Vakil, Deputy Director and Senior Research Fellow, Middle East and North Africa Programme, Chatham House This webinar, part of the MENA Programme Webinar Series, will examine the trajectory of political and security dynamics in the Gulf in view of the ongoing rift within the Gulf Cooperation Council (GCC), the death of Sultan Qaboos in Oman, the escalation of tensions between Iran and the United States, and the COVID-19 crisis.Speakers will explore the orientation of the GCC under a new Secretary-General and the prospects for mediation between Qatar and its neighbours, the future of Omani domestic and foreign policy under Sultan Haitham bin Tariq Al Said, eventual transitions to new leadership in Bahrain and Kuwait, and whether the impact of COVID-19 may help replace the confrontation within the GCC with closer coordination among its six member states.The webinar will be livestreamed on the MENA Programme Facebook page. Department/project Middle East and North Africa Programme, Future Dynamics in the Gulf Reni Zhelyazkova Programme Coordinator, Middle East and North Africa Programme +44 (0)20 7314 3624 Email Full Article
Reni Zhelyazkova Programme Coordinator, Middle East and North Africa Programme +44 (0)20 7314 3624 Email
do Webinar: Idlib at Risk – Doctors and First Responders in Northwest Syria By feedproxy.google.com Published On :: Thu, 16 Apr 2020 08:55:01 +0000 Members Event Webinar 23 April 2020 - 5:00pm to 6:00pm Online Event participants Dr Munzer al-Khalil, Head, Idlib Health DirectorateRaed Al Saleh, Director, Syria Civil Defence (The White Helmets)Alaa Rajaa Mughrabieh, Child Protection Officer, Hurras NetworkChair: Dr Lina Khatib, Director, Middle East and North Africa Programme, Chatham House In Syria, uncertainty about the safety of the ceasefire agreed between Russia and Turkey last month is inhibiting 1 million people who have been displaced since December 2019 from returning home.The looming COVID-19 global health crisis threatens to further devastate those most vulnerable as the conditions in northwest Syria’s refugee camps make it hard to practice common social distancing guidelines. Added to this, the medical infrastructure in the region has been decimated after years of bombings which has disabled over 70 health facilities since April 2019.This webinar highlights the potentially catastrophic risks of a coronavirus outbreak in Idlib and displacement camps in northwest Syria by speaking with medical and civil society actors working in the region. How are doctors and local humanitarian organizations scaling up their medical and prevention response to the COVID-19 outbreak?What key supplies such as ventilators, testing kits and critical sanitary equipment are still lacking? And how can the international community step in to help mitigate the potentially devastating consequences of an outbreak in these refugee camps?This event is run in collaboration with The Syria Campaign, a human rights organization working with Syrian civil society to raise the voices of those struggling for democracy, and support frontline activists and humanitarians. Full Article
do Webinar: Does COVID-19 Spell the End of America's Interest in Globalization? By feedproxy.google.com Published On :: Mon, 20 Apr 2020 09:40:01 +0000 Research Event 19 May 2020 - 2:00pm to 3:00pmAdd to CalendariCalendar Outlook Google Yahoo Dr Anne-Marie Slaughter, CEO, New AmericaProfessor Stephen Walt, Robert and Renee Belfer Professor of International Affairs, Harvard Kennedy SchoolChair: Dr Leslie Vinjamuri, Director, US and Americas Programme, Chatham House This event is part of the US and Americas Programme Inaugural Virtual Roundtable Series on the US and the State of the World and will take place virtually only. Please note this event is taking place between 2pm to 3pm BST. US and Americas Programme Email Department/project US and the Americas Programme Full Article
do Virtual Roundtable: Re-integration or Dis-integration: What Does the Future Hold for Occupied Donbas? By feedproxy.google.com Published On :: Tue, 21 Apr 2020 22:55:01 +0000 Invitation Only Research Event 28 April 2020 - 4:00pm to 5:30pm Event participants Paul D’anieri, Professor of Public Policy and Political Science, University of California, RiversideVlad Mykhnenko, Associate Professor of Sustainable Urban Development, St Peter’s College, University of OxfordChair: Orysia Lutsevych, Research Fellow and Manager, Ukraine Forum, Chatham House The armed conflict in Donbas has now entered its seventh year. President Zelenskyy, who came to power in May 2019, promised to end the war with Russia and bring peace to Ukraine.Since assuming office, Zelenskyy has managed to revive the Normandy Format talks, complete military disengagement at three points along the line of contact and negotiate the release of over a hundred Ukrainians held as prisoners of war in Russia. However, ceasefire violations continue to occur frequently.Looking at the origins of the armed conflict in Donbas and the region’s economic role in Ukraine’s economy, this event discusses the prospects for conflict resolution. Do the recent events signify an opportunity for peace? Does Zelenskyy have a viable plan for re-integrating Donbas or will the region be cut off from mainland Ukraine for the foreseeable future?The speakers assess the strategy and track record of the Ukrainian government and its Western allies in bringing parts of the occupied Donbas under Kyiv’s control. They also review possible policy implications of the COVID-19 pandemic for the conflict. Department/project Russia and Eurasia Programme, Ukraine Forum Anna Morgan Administrator, Ukraine Forum +44 (0)20 7389 3274 Email Full Article
do The certainties that underpin the Kingdom need reappraisal By feedproxy.google.com Published On :: Wed, 05 Feb 2014 15:54:42 +0000 6 February 2014 , Volume 70, Number 1 From the point of view of a Saudi policy-maker, the country, the region and the world look to be increasingly complex places Sir Tom Phillips, British Ambassador to Saudi Arabia 2010-12 Phillips_0.jpg Saudi Arabia's King Abdullah in discussions with John Kerry, the US Secretary of State. Photo: Brendan Smialowski/AFP/Getty Full Article
do Human Development as Positive Freedom: A World View Since 1870 By feedproxy.google.com Published On :: Mon, 10 Feb 2014 15:33:29 +0000 Invitation Only 26 February 2014 - 8:15am to 9:30am Chatham House, London Event participants Leandro Prados de la Escosura, Professor, Economic History, Universidad Carlos III de Madrid This meeting will see the launch of the Chatham House-CAGE briefing paper ‘Human Development as Positive Freedom: A World View since 1870’. The author of the paper will argue that while substantial gains in world human development have been achieved since 1870, the main period of improvement actually occurred between World War I and 1970. He will further argue that, despite initial successes in lifting human development, the socialist experiments of the 20th century failed to sustain momentum and then (with the exception of Cuba) stagnated and fell behind prior to the socialist model's ultimate demise. Finally, he will contend that since 1970, while most OECD countries have experienced a second (later life) health transition, all developing regions have fallen behind in this dimension.The briefing paper is the 12th publication in the Chatham House-CAGE series, published in partnership with the Centre for Competitive Advantage in the Global Economy (CAGE) at the University of Warwick.Attendance at this event is by invitation only. Department/project Global Economy and Finance Programme Full Article
do Human Development as Positive Freedom: A World View Since 1870 By feedproxy.google.com Published On :: Thu, 27 Feb 2014 15:32:11 +0000 1 February 2014 Substantial gains in world human development have been achieved since 1870, but research shows that the main improvement actually occurred between the First World War and 1970. Leandro Prados de la Escosura 20140200CAGEhumandevelopmentW.jpg Photo by 1xpert /iStock. Summary points:Substantial gains in world human development have been achieved since 1870, but research shows that the main improvement actually occurred between the First World War and 1970. Across-the-board advances took place in life expectancy and education between 1920 and 1950, a phase during which there was a major backlash against economic globalization. This is evidence of a development puzzle: economic growth and human development do not always go hand in hand. Between 1913 and 1970 the absolute gap between most countries in the OECD and the rest of the world widened, with different regions experiencing mixed success in catching up. Since the 1970s the performance of developing regions has varied greatly. Despite initial successes in lifting human development, the socialist experiments of the 20th century failed to sustain momentum and then (with the exception of Cuba) stagnated and fell behind prior to the socialist model’s ultimate demise. Education has been the driving force behind the limited catching-up of developing regions in terms of long-term human development. In terms of life expectancy,these regions achieved significant gains only during the first (early-life) health transition. Since 1970, while most OECD countries have experienced a second (later-life) health transition, all developing regions have fallen behind.Project: Shifting Competitive Advantage in the Global Economy Launch eventHuman Development as Positive Freedom: A World View Since 187026 February 2014 Related documents Briefing Paper: Human Development as Positive Freedom: A World View Since 1870pdf | 666.29 KB Department/project Global Economy and Finance Programme, Shifting Competitive Advantage in the Changing Global Economy Full Article
do Lesotho’s Domestic Priorities and Global Interests: Small Country Levers for International Influence By feedproxy.google.com Published On :: Tue, 01 Apr 2014 14:57:42 +0000 Research Event 7 April 2014 - 3:00pm to 4:00pm Chatham House, London Meeting Summarypdf | 59.43 KB Event participants HE Dr Motsoahae Thomas Thabane, Prime Minister of LesothoChair: Ian Lucas MP, Shadow Minister for Africa and the Middle East The landlocked southern African nation of Lesotho faces a number of domestic challenges in 2014. Reducing reliance on the agricultural sector, containing the prevalence of HIV and improving service delivery are all important issues that must be addressed to ensure sustainable growth. However, social achievements including literacy rates and levels of gender parity among the highest in Africa, the country’s potential for electricity exports, and the booming relationship between its textile industry and the United States, could mean Lesotho is well-placed for future growth and development. HE Prime Minister Tom Thabane will discuss how his government seeks to address the Lesotho’s domestic issues and how the country seeks to exert its influence in the regional Southern African Development Community. Full Article
do Stifling the Media: Barriers to Press Freedom By feedproxy.google.com Published On :: Thu, 10 Apr 2014 16:19:46 +0000 Under 35s Forum 20 May 2014 - 6:30pm to 7:30pm Chatham House, London Transcriptpdf | 77.33 KB Transcript Q&Apdf | 72.27 KB Event participants Yavuz Baydar, Columnist, Today's Zaman; Co-Founder, P24, Platform for Independent Journalism; Recipient, Special Award of the European Press Prize James Deane, Director of Policy and Learning, BBC Media ActionKirsty Hughes, Writer; Chief Executive, Index on Censorship (2012-14)Chair: John Lloyd, Contributing Editor, Financial Times; Director of Journalism, Reuters Institute for the Study of Journalism From intimidation to restrictive laws and curbs on information, media outlets and individual journalists face a variety of threats to maintaining their independence and integrity in print and online. The panel will outline key challenges to international media freedoms, and Yavuz Baydar will share his experiences as a journalist in Turkey, a country that has faced growing criticism from the international community following a crackdown on social media sites, an increased pressure on its press and high numbers of detained journalists. LIVE STREAM: This event will be live streamed for members only. The live stream will be made available here at 18:30 BST on Tuesday 20 May.ASK A QUESTION: Send questions for the speakers by email to questions@chathamhouse.org or using #askCH on Twitter. A selection will be put to them during the event.This event will be followed by a reception.This is an Under 35s Forum event. Event attributes Livestream Full Article
do Abkhazia: Developments in the Domestic and Regional Context By feedproxy.google.com Published On :: Thu, 09 Oct 2014 12:45:01 +0000 Invitation Only Research Event 14 October 2014 - 10:00am to 11:30am Chatham House, London Meeting Summarypdf | 40.6 KB Event participants Viacheslav Chirikba, de facto Minister of Foreign Affairs, Abkhazia Viacheslav Chirikba will offer his perspective on the situation in Abkhazia following the recent presidential elections, and the developments in Abkhazia's relations with other regional players. Attendance at this event is by invitation only. Lubica Pollakova +44 (0)20 7314 2775 Email Full Article
do Challenges to Freedom of Expression By feedproxy.google.com Published On :: Tue, 21 Jun 2016 10:00:01 +0000 Research Event 20 July 2016 - 6:00pm to 7:15pm Chatham House, London Meeting Summarypdf | 107.63 KB Event participants Sherif Elsayed-Ali, Head of Technology and Human Rights, Amnesty InternationalProfessor David Kaye, UN Special Rapporteur on the Promotion and Protection of the Right to Freedom of Opinion and ExpressionChair: Sonya Sceats, Associate Fellow, International Law Programme, Chatham House The digital age has seen an extraordinary transformation in how individuals can exercise their right to freedom of expression. What are the proper limits of state interference in online communication in pursuit of national security and public order? What does this mean for privacy? And away from the digital world, to what extent is free speech being affected by counterterrorism measures and actions to prevent hate crimes? How do all of these challenges affect the space for civil society action? Department/project International Law Programme, Rights, Accountability and Justice, International Law Discussion Group Chanu Peiris Programme Manager, International Law +44 (0)20 7314 3686 Email Full Article
do History for Fantasy Writers: Do You Have a Moment? By mythicscribes.com Published On :: Sun, 16 Feb 2020 20:35:37 +0000 This is the second part of a two-part article on how time was perceived and measured in ancient and medieval Europe. In the last installment of History for Fantasy Writers I addressed years, months, weeks, and days. Now I turn to shorter lengths: days, hours and still shorter periods. I’ll close with a more general consideration of time and the awareness of time. Hours We carve the day into twenty-four hours, but in the past the hour was a malleable thing. There were twelve hours of daylight and twelve hours of night, regardless of the season. The day began with zero at sunrise. Then came the first hour, the second, and so on. The twelfth hour fell at sunset. A winter daylight hour was therefore shorter than a summer hour. This feels a little nuts at first, but it’s actually pretty sensible. At least the word midnight makes sense in that system—it’s the mid-point of the night, regardless of how long is the night. All we have to do is abandon the notion that an hour is a unit of time, to consider it as marking portions of a day. Continue reading History for Fantasy Writers: Do You Have a Moment? at Mythic Scribes. Full Article History history for fantasy writers how time was perceived and measured
do Cytochrome P450 and arachidonic acid bioactivation: molecular and functional properties of the arachidonate monooxygenase By feedproxy.google.com Published On :: 2000-02-01 Jorge H. CapdevilaFeb 1, 2000; 41:163-181Reviews Full Article
do Disruption of endoplasmic reticulum structure and integrity in lipotoxic cell death By feedproxy.google.com Published On :: 2006-12-01 Nica M. BorradaileDec 1, 2006; 47:2726-2737Research Articles Full Article
do Marked reduction in bile acid synthesis in cholesterol 7{alpha}-hydroxylase-deficient mice does not lead to diminished tissue cholesterol turnover or to hypercholesterolemia By feedproxy.google.com Published On :: 1998-09-01 Margrit SchwarzSep 1, 1998; 39:1833-1843Articles Full Article
do Lipidomics reveals a remarkable diversity of lipids in human plasma By feedproxy.google.com Published On :: 2010-11-01 Oswald QuehenbergerNov 1, 2010; 51:3299-3305Research Articles Full Article
do Lipid extraction by methyl-tert-butyl ether for high-throughput lipidomics By feedproxy.google.com Published On :: 2008-05-01 Vitali MatyashMay 1, 2008; 49:1137-1146Methods Full Article
do Immature leadership: Donald Trump and the American presidency By feedproxy.google.com Published On :: Wed, 04 Mar 2020 13:20:12 +0000 4 March 2020 , Volume 96, Number 2 Read online Daniel W. Drezner There has been a renaissance in the study of how the backgrounds of individual leaders affect foreign policy outcomes. Donald Trump's presidency highlights the limits of this approach. Trump's psychology is so unique, and so akin to that of a small child, that studying his background alone is insufficient to explain his decision-making. The evidence for this characterization of Trump's leadership comes not from his political opponents, but his allies, staffers and subordinates. Trump's lack of impulse control, short attention span and frequent temper tantrums have all undercut his effectiveness as president as compared to his predecessors. Nonetheless, the 45th president helps to clarify ongoing debates in American politics about the relative strength of the presidency as an institution. In particular, the powers of the presidency have become so enhanced that even comparatively weak and inexperienced leaders can execute dramatic policy shifts. The formal checks on presidential power, from the legislative, judicial and executive branches have all eroded. Similarly, the informal checks on the presidency had also degraded before Trump's inauguration. This article uses Trump's presidency—and his severe limitations as a decision-maker—to highlight the ways in which even a weak leader can affect change by holding a powerful office. Full Article
do WHO Can Do Better - But Halting Funding is No Answer By feedproxy.google.com Published On :: Mon, 20 Apr 2020 09:11:18 +0000 20 April 2020 Dr Charles Clift Senior Consulting Fellow, Global Health Programme @CliftWorks Calling a halt to funding for an unspecified time is an unsatisfactory halfway house for the World Health Organization (WHO) to deal with. But with Congress and several US agencies heavily involved, whether a halt is even feasible is under question. 2020-04-20-PPE-Ethiopia-WHO Checking boxes of personal protective equipment (PPE) at the Bole International Airport in Addis Ababa, Ethiopia. Photo by SAMUEL HABTAB/AFP via Getty Images. Donald Trump is impulsive. His sudden decision to stop funding the World Health Organization (WHO) just days after calling it 'very China-centric” and 'wrong about a lot of things' is the latest example. And this in the midst of the worst pandemic since Spanish flu in 1918 and a looming economic crisis compared by some to the 1930s. But the decision is not really just about what WHO might or might not have done wrong. It is more about the ongoing geopolitical wrangle between the US and China, and about diverting attention from US failings in its own response to coronavirus in the run-up to the US presidential election.It clearly also derives from Trump’s deep antipathy to almost any multilateral organization. WHO has been chosen as the fall guy in this political maelstrom in a way that might please Trump’s supporters who will have read or heard little about WHO’s role in tackling this crisis. And the decision has been widely condemned in almost all other countries and by many in the US.What is it likely to mean in practice for WHO?Calling a halt to funding for an unspecified time is an unsatisfactory halfway house. A so-called factsheet put out by the White House talks about the reforms it thinks necessary 'before the organization can be trusted again'. This rather implies that the US wants to remain a member of WHO if it can achieve the changes it wants. Whether those changes are feasible is another question — they include holding member states accountable for accurate data-sharing and countering what is referred to as 'China’s outsize influence on the organization'. Trump said the funding halt would last while WHO’s mismanagement of the coronavirus pandemic was investigated, which would take 60-90 days. The US is the single largest funder of WHO, providing about 16% of its budget. It provides funds to WHO in two ways. The first is the assessed contribution — the subscription each country pays to be a member. In 2018/19 the US contribution should have been $237 million but, as of January this year it was in arrears by about $200 million.Much bigger are US voluntary contributions provided to WHO for specified activities amounting in the same period to another $650 million. These are for a wide variety of projects — more than one-quarter goes to polio eradication, but a significant portion also is for WHO’s emergency work. The US assessed contribution represents only 4% of WHO’s budget. Losing that would certainly be a blow to WHO but a manageable one. Given the arrears situation it is not certain that the US would have paid any of this in the next three months in any case. More serious would be losing the US voluntary contributions which account for about another 12% of WHO’s budget—but whether this could be halted all at once is very unclear. First Congress allocates funds in the US, not the president, raising questions about how a halt could be engineered domestically.Secondly, US contributions to WHO come from about ten different US government agencies, such as the National Institutes of Health or USAID, each of whom have separate agreements with WHO. Will they be prepared to cut funding for ongoing projects with WHO? And does the US want to disrupt ongoing programmes such as polio eradication and, indeed, emergency response which contribute to saving lives? Given the president’s ability to do 180 degree U-turns we shall have to wait and see what will actually happen in the medium term. If it presages the US leaving WHO, this would only facilitate growing Chinese influence in the WHO and other UN bodies. Perhaps in the end wiser advice will be heeded and a viable solution found.Most of President Trump’s criticisms of WHO do not bear close scrutiny. WHO may have made mistakes — it may have given too much credence to information coming from the Chinese. China has just announced that the death toll in Wuhan was 50% higher than previously revealed. It may have overpraised China’s performance and system, but this was part of a deliberate strategy to secure China’s active collaboration so that it could help other countries learn from China’s experience. The chief message from this sorry story is that two countries are using WHO as a pawn in pursuing their respective political agendas which encompass issues well beyond the pandemic. China has been very successful in gaining WHO’s seal of approval, in spite of concerns about events prior to it declaring the problem to the WHO and the world. This, in turn, has invited retaliation from the US. When this is over will be the time to learn lessons about what WHO should have done better. But China, the US, and the global community of nations also need to consider their own responsibility in contributing to this terrible unfolding tragedy.This article was originally published in the British Medical Journal Full Article
do Webinar: Does COVID-19 Spell the End of America's Interest in Globalization? By feedproxy.google.com Published On :: Mon, 20 Apr 2020 09:40:01 +0000 Research Event 19 May 2020 - 2:00pm to 3:00pmAdd to CalendariCalendar Outlook Google Yahoo Dr Anne-Marie Slaughter, CEO, New AmericaProfessor Stephen Walt, Robert and Renee Belfer Professor of International Affairs, Harvard Kennedy SchoolChair: Dr Leslie Vinjamuri, Director, US and Americas Programme, Chatham House This event is part of the US and Americas Programme Inaugural Virtual Roundtable Series on the US and the State of the World and will take place virtually only. Please note this event is taking place between 2pm to 3pm BST. US and Americas Programme Email Department/project US and the Americas Programme Full Article
do Dopamine transporter trafficking and Rit2 GTPase: Mechanism of action and in vivo impact [Neurobiology] By feedproxy.google.com Published On :: 2020-04-17T00:06:05-07:00 Following its evoked release, dopamine (DA) signaling is rapidly terminated by presynaptic reuptake, mediated by the cocaine-sensitive DA transporter (DAT). DAT surface availability is dynamically regulated by endocytic trafficking, and direct protein kinase C (PKC) activation acutely diminishes DAT surface expression by accelerating DAT internalization. Previous cell line studies demonstrated that PKC-stimulated DAT endocytosis requires both Ack1 inactivation, which releases a DAT-specific endocytic brake, and the neuronal GTPase, Rit2, which binds DAT. However, it is unknown whether Rit2 is required for PKC-stimulated DAT endocytosis in DAergic terminals or whether there are region- and/or sex-dependent differences in PKC-stimulated DAT trafficking. Moreover, the mechanisms by which Rit2 controls PKC-stimulated DAT endocytosis are unknown. Here, we directly examined these important questions. Ex vivo studies revealed that PKC activation acutely decreased DAT surface expression selectively in ventral, but not dorsal, striatum. AAV-mediated, conditional Rit2 knockdown in DAergic neurons impacted baseline DAT surface:intracellular distribution in DAergic terminals from female ventral, but not dorsal, striatum. Further, Rit2 was required for PKC-stimulated DAT internalization in both male and female ventral striatum. FRET and surface pulldown studies in cell lines revealed that PKC activation drives DAT-Rit2 surface dissociation and that the DAT N terminus is required for both PKC-mediated DAT-Rit2 dissociation and DAT internalization. Finally, we found that Rit2 and Ack1 independently converge on DAT to facilitate PKC-stimulated DAT endocytosis. Together, our data provide greater insight into mechanisms that mediate PKC-regulated DAT internalization and reveal unexpected region-specific differences in PKC-stimulated DAT trafficking in bona fide DAergic terminals. Full Article
do G{alpha}q splice variants mediate phototransduction, rhodopsin synthesis, and retinal integrity in Drosophila [Signal Transduction] By feedproxy.google.com Published On :: 2020-04-24T06:08:45-07:00 Heterotrimeric G proteins mediate a variety of signaling processes by coupling G protein–coupled receptors to intracellular effector molecules. In Drosophila, the Gαq gene encodes several Gαq splice variants, with the Gαq1 isoform protein playing a major role in fly phototransduction. However, Gαq1 null mutant flies still exhibit a residual light response, indicating that other Gαq splice variants or additional Gq α subunits are involved in phototransduction. Here, we isolated a mutant fly with no detectable light responses, decreased rhodopsin (Rh) levels, and rapid retinal degeneration. Using electrophysiological and genetic studies, biochemical assays, immunoblotting, real-time RT-PCR, and EM analysis, we found that mutations in the Gαq gene disrupt light responses and demonstrate that the Gαq3 isoform protein is responsible for the residual light response in Gαq1 null mutants. Moreover, we report that Gαq3 mediates rhodopsin synthesis. Depletion of all Gαq splice variants led to rapid light-dependent retinal degeneration, due to the formation stable Rh1-arrestin 2 (Arr2) complexes. Our findings clarify essential roles of several different Gαq splice variants in phototransduction and retinal integrity in Drosophila and reveal that Gαq3 functions in rhodopsin synthesis. Full Article
do Roles of the DOCK-D family proteins in a mouse model of neuroinflammation [Neurobiology] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 The DOCK-D (dedicator of cytokinesis D) family proteins are atypical guanine nucleotide exchange factors that regulate Rho GTPase activity. The family consists of Zizimin1 (DOCK9), Zizimin2 (DOCK11), and Zizimin3 (DOCK10). Functions of the DOCK-D family proteins are presently not well-explored, and the role of the DOCK-D family in neuroinflammation is unknown. In this study, we generated three mouse lines in which DOCK9 (DOCK9−/−), DOCK10 (DOCK10−/−), or DOCK11 (DOCK11−/−) had been deleted and examined the phenotypic effects of these gene deletions in MOG35–55 peptide-induced experimental autoimmune encephalomyelitis, an animal model of the neuroinflammatory disorder multiple sclerosis. We found that all the gene knockout lines were healthy and viable. The only phenotype observed under normal conditions was a slightly smaller proportion of B cells in splenocytes in DOCK10−/− mice than in the other mouse lines. We also found that the migration ability of macrophages is impaired in DOCK10−/− and DOCK11−/− mice and that the severity of experimental autoimmune encephalomyelitis was ameliorated only in DOCK10−/− mice. No apparent phenotype was observed for DOCK9−/− mice. Further investigations indicated that lipopolysaccharide stimulation up-regulates DOCK10 expression in microglia and that microglial migration is decreased in DOCK10−/− mice. Up-regulation of C–C motif chemokine ligand 2 (CCL2) expression induced by activation of Toll-like receptor 4 or 9 signaling was reduced in DOCK10−/− astrocytes compared with WT astrocytes. Taken together, our findings suggest that DOCK10 plays a role in innate immunity and neuroinflammation and might represent a potential therapeutic target for managing multiple sclerosis. Full Article
do Coronavirus: Public Health Emergency or Pandemic – Does Timing Matter? By feedproxy.google.com Published On :: Fri, 01 May 2020 14:48:43 +0000 1 May 2020 Dr Charles Clift Senior Consulting Fellow, Global Health Programme @CliftWorks The World Health Organization (WHO) has been criticized for delaying its announcements of a public health emergency and a pandemic for COVID-19. But could earlier action have influenced the course of events? 2020-05-01-Tedros-WHO-COVID WHO director-general Dr Tedros Adhanom Ghebreyesus at the COVID-19 press briefing on March 11, 2020, the day the coronavirus outbreak was classed as a pandemic. Photo by FABRICE COFFRINI/AFP via Getty Images. The World Health Organization (WHO) declared the spread of COVID-19 to be a Public Health Emergency of International Concern (PHEIC) on January 30 this year and then characterized it as a pandemic on March 11.Declaring a PHEIC is the highest level of alert that WHO is obliged to declare, and is meant to send a powerful signal to countries of the need for urgent action to combat the spread of the disease, mobilize resources to help low- and middle-income countries in this effort and fund research and development on needed treatments, vaccines and diagnostics. It also obligates countries to share information with WHO.Once the PHEIC was declared, the virus continued to spread globally, and WHO began to be asked why it had not yet declared the disease a pandemic. But there is no widely accepted definition of a pandemic, generally it is just considered an epidemic which affects many countries globally.Potentially more deadlyThe term has hitherto been applied almost exclusively to new forms of flu, such as H1N1 in 2009 or Spanish flu in 1918, where the lack of population immunity and absence of a vaccine or effective treatments makes the outbreak potentially much more deadly than seasonal flu (which, although global, is not considered a pandemic).For COVID-19, WHO seemed reluctant to declare a pandemic despite the evidence of global spread. Partly this was because of its influenza origins — WHO’s emergency programme executive director said on March 9 that ‘if this was influenza, we would have called a pandemic ages ago’.He also expressed concern that the word traditionally meant moving — once there was widespread transmission — from trying to contain the disease by testing, isolating the sick and tracing and quarantining their contacts, to a mitigation approach, implying ‘the disease will spread uncontrolled’.WHO’s worry was that the world’s reaction to the word pandemic might be there was now nothing to be done to stop its spread, and so countries would effectively give up trying. WHO wanted to send the message that, unlike flu, it could still be pushed back and the spread slowed down.In announcing the pandemic two days later, WHO’s director-general Dr Tedros Adhanom Ghebreyesus reemphasised this point: ‘We cannot say this loudly enough, or clearly enough, or often enough: all countries can still change the course of this pandemic’ and that WHO was deeply concerned ‘by the alarming levels of inaction’.The evidence suggests that the correct message did in fact get through. On March 13, US president Donald Trump declared a national emergency, referring in passing to WHO’s announcement. On March 12, the UK launched its own strategy to combat the disease. And in the week following WHO’s announcements, at least 16 other countries announced lockdowns of varying rigour including Austria, Belgium, Canada, Czech Republic, Denmark, Finland, France, Germany, Hungary, Netherlands, Norway, Poland, Portugal, Serbia, Spain and Switzerland. Italy and Greece had both already instituted lockdowns prior to the WHO pandemic announcement.It is not possible to say for sure that WHO’s announcement precipitated these measures because, by then, the evidence of the rapid spread was all around for governments to see. It may be that Italy’s dramatic nationwide lockdown on March 9 reverberated around European capitals and elsewhere.But it is difficult to believe the announcement did not have an effect in stimulating government actions, as was intended by Dr Tedros. Considering the speed with which the virus was spreading from late February, might an earlier pandemic announcement by WHO have stimulated earlier aggressive actions by governments?Declaring a global health emergency — when appropriate — is a key part of WHO’s role in administering the International Health Regulations (IHR). Significantly, negotiations on revisions to the IHR, which had been ongoing in a desultory fashion in WHO since 1995, were accelerated by the experience of the first serious coronavirus outbreak — SARS — in 2002-2003, leading to their final agreement in 2005.Under the IHR, WHO’s director-general decides whether to declare an emergency based on a set of criteria and on the advice of an emergency committee. IHR defines an emergency as an ‘extraordinary event that constitutes a public health risk through the international spread of disease and potentially requires a coordinated international response’.In the case of COVID-19, the committee first met on January 22-23 but were unable to reach consensus on a declaration. Following the director-general’s trip to meet President Xi Jinping in Beijing, the committee reconvened on January 30 and this time advised declaring a PHEIC.But admittedly, public recognition of what a PHEIC means is extremely low. Only six have ever been declared, with the first being the H1N1 flu outbreak which fizzled out quickly, despite possibly causing 280,000 deaths globally. During the H1N1 outbreak, WHO declared a PHEIC in April 2009 and then a pandemic in June, only to rescind both in August as the outbreak was judged to have transitioned to behave like a seasonal flu.WHO was criticized afterwards for prematurely declaring a PHEIC and overreacting. This then may have impacted the delay in declaring the Ebola outbreak in West Africa as a PHEIC in 2014, long after it became a major crisis. WHO’s former legal counsel has suggested the PHEIC — and other aspects of the IHR framework — may not be effective in stimulating appropriate actions by governments and needs to be reconsidered.When the time is right to evaluate lessons about the response, it might be appropriate to consider the relative effectiveness of the PHEIC and pandemic announcements and their optimal timing in stimulating appropriate action by governments. The effectiveness of lockdowns in reducing the overall death toll also needs investigation. Full Article
do The Centenary London Conference By feedproxy.google.com Published On :: Thu, 18 Jun 2020 10:45:46 +0000 Thursday 19 and Friday 20 November 2020, St. Pancras Renaissance HotelOne hundred years since its founding in 1920, Chatham House continues to foster mutual understanding between nations through rigorous debate, trusted dialogue, independent analysis and influential ideas. Since its launch in 2014, the London Conference, the institute’s annual flagship event, has established itself as a principal international forum where global connectivity can be explored and better understood drawing an internationally diverse and multigenerational gathering of participants and offering positive solutions to global challenges.This year, drawing on the theme of Imagining Alternatives: Solutions for the World Beyond 2020, the London Conference 2020 will form the central pillar in the institute’s programme to mark its centenary throughout 2020. This year’s agenda focuses on the changing nature of geopolitics and the global economy through the lens of our core research themes – sustainable and equitable growth, preventing conflict and improving the rules-based order. Each theme seeks opportunities for positive policy change, with emphasis on the impact of technological change, and a keen focus on empowering the next generation. The Centenary London Conference Agenda 23 January 2020 One hundred years since its founding in 1920, Chatham House continues to foster mutual understanding between nations through rigorous debate, trusted dialogue, independent analysis and influential ideas. About The London Conference 20 January 2016 The Chatham House London Conference is the institute’s annual flagship event and is established as a principal international forum where global connectivities can be explored and better understood. Sponsors 17 March 2015 The London Conference is supported by a small group of major multinational companies with extensive international interests and experience. Speakers 23 January 2019 Speakers for 2020 will be announced shortly. Past Conferences 12 March 2018 Browse content from past London Conferences since its beginnings in 2014. Full Article