hi

GPS 2.0, a Tool to Predict Kinase-specific Phosphorylation Sites in Hierarchy

Yu Xue
Sep 1, 2008; 7:1598-1608
Research




hi

Highly Selective Enrichment of Phosphorylated Peptides from Peptide Mixtures Using Titanium Dioxide Microcolumns

Martin R. Larsen
Jul 1, 2005; 4:873-886
Technology




hi

The Human Plasma Proteome: History, Character, and Diagnostic Prospects

N. Leigh Anderson
Nov 1, 2002; 1:845-867
Reviews/Perspectives




hi

The hibernating 100S complex is a target of ribosome-recycling factor and elongation factor G in Staphylococcus aureus [Protein Synthesis and Degradation]

The formation of translationally inactive 70S dimers (called 100S ribosomes) by hibernation-promoting factor is a widespread survival strategy among bacteria. Ribosome dimerization is thought to be reversible, with the dissociation of the 100S complexes enabling ribosome recycling for participation in new rounds of translation. The precise pathway of 100S ribosome recycling has been unclear. We previously found that the heat-shock GTPase HflX in the human pathogen Staphylococcus aureus is a minor disassembly factor. Cells lacking hflX do not accumulate 100S ribosomes unless they are subjected to heat exposure, suggesting the existence of an alternative pathway during nonstressed conditions. Here, we provide biochemical and genetic evidence that two essential translation factors, ribosome-recycling factor (RRF) and GTPase elongation factor G (EF-G), synergistically split 100S ribosomes in a GTP-dependent but tRNA translocation-independent manner. We found that although HflX and the RRF/EF-G pair are functionally interchangeable, HflX is expressed at low levels and is dispensable under normal growth conditions. The bacterial RRF/EF-G pair was previously known to target only the post-termination 70S complexes; our results reveal a new role in the reversal of ribosome hibernation that is intimately linked to bacterial pathogenesis, persister formation, stress responses, and ribosome integrity.




hi

{gamma}-Hydroxybutyrate does not mediate glucose inhibition of glucagon secretion [Signal Transduction]

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.




hi

12-LOX catalyzes the oxidation of 2-arachidonoyl-lysolipids in platelets generating eicosanoid-lysolipids that are attenuated by iPLA2{gamma} knockout [Signal Transduction]

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.




hi

G{alpha}q splice variants mediate phototransduction, rhodopsin synthesis, and retinal integrity in Drosophila [Signal Transduction]

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.




hi

Biophysical characterization of SARAH domain-mediated multimerization of Hippo pathway complexes in Drosophila [Signal Transduction]

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.




hi

The focal adhesion protein kindlin-2 controls mitotic spindle assembly by inhibiting histone deacetylase 6 and maintaining {alpha}-tubulin acetylation [Signal Transduction]

Kindlins are focal adhesion proteins that regulate integrin activation and outside-in signaling. The kindlin family consists of three members, kindlin-1, -2, and -3. Kindlin-2 is widely expressed in multiple cell types, except those from the hematopoietic lineage. A previous study has reported that the Drosophila Fit1 protein (an ortholog of kindlin-2) prevents abnormal spindle assembly; however, the mechanism remains unknown. Here, we show that kindlin-2 maintains spindle integrity in mitotic human cells. The human neuroblastoma SH-SY5Y cell line expresses only kindlin-2, and we found that when SH-SY5Y cells are depleted of kindlin-2, they exhibit pronounced spindle abnormalities and delayed mitosis. Of note, acetylation of α-tubulin, which maintains microtubule flexibility and stability, was diminished in the kindlin-2–depleted cells. Mechanistically, we found that kindlin-2 maintains α-tubulin acetylation by inhibiting the microtubule-associated deacetylase histone deacetylase 6 (HDAC6) via a signaling pathway involving AKT Ser/Thr kinase (AKT)/glycogen synthase kinase 3β (GSK3β) or paxillin. We also provide evidence that prolonged hypoxia down-regulates kindlin-2 expression, leading to spindle abnormalities not only in the SH-SY5Y cell line, but also cell lines derived from colon and breast tissues. The findings of our study highlight that kindlin-2 regulates mitotic spindle assembly and that this process is perturbed in cancer cells in a hypoxic environment.




hi

Small-molecule agonists of the RET receptor tyrosine kinase activate biased trophic signals that are influenced by the presence of GFRa1 co-receptors [Neurobiology]

Glial cell line–derived neurotrophic factor (GDNF) is a growth factor that regulates the health and function of neurons and other cells. GDNF binds to GDNF family receptor α1 (GFRa1), and the resulting complex activates the RET receptor tyrosine kinase and subsequent downstream signals. This feature restricts GDNF activity to systems in which GFRa1 and RET are both present, a scenario that may constrain GDNF breadth of action. Furthermore, this co-dependence precludes the use of GDNF as a tool to study a putative functional cross-talk between GFRa1 and RET. Here, using biochemical techniques, terminal deoxynucleotidyl transferase dUTP nick end labeling staining, and immunohistochemistry in murine cells, tissues, or retinal organotypic cultures, we report that a naphthoquinone/quinolinedione family of small molecules (Q compounds) acts as RET agonists. We found that, like GDNF, signaling through the parental compound Q121 is GFRa1-dependent. Structural modifications of Q121 generated analogs that activated RET irrespective of GFRa1 expression. We used these analogs to examine RET–GFRa1 interactions and show that GFRa1 can influence RET-mediated signaling and enhance or diminish AKT Ser/Thr kinase or extracellular signal-regulated kinase signaling in a biased manner. In a genetic mutant model of retinitis pigmentosa, a lead compound, Q525, afforded sustained RET activation and prevented photoreceptor neuron loss in the retina. This work uncovers key components of the dynamic relationships between RET and its GFRa co-receptor and provides RET agonist scaffolds for drug development.




hi

The Rise of China and the Future of the Transatlantic Relationship

29 July 2019

The growth of China's wealth and military power represents an epochal change in international politics. This briefing argues that China’s rise has worrying implications for the liberal international order and explores how this will affect the transatlantic relationship.

Jennifer Lind

Associate Fellow, US and the Americas Programme and Asia-Pacific Programme (based in the US)

2019-07-29-RiseOfChina.jpg

Teams from France, Great Britain, the US, China, Australia and Japan race against each other during the SailGP on 4 May 2019 in San Francisco, California. Photo: Getty Images

Summary

  • The stakeholders in the transatlantic relationship – the US, Canada and Europe – have long sought to stabilize international politics and economies by spreading support for the liberal goals of free markets, democracy and human rights. As their own commitment to this agenda appears to waver, China is becoming wealthier and more assertive. This briefing explores the extent to which these goals – along with the unity of the transatlantic relationship – are now in jeopardy.
  • Great uncertainty surrounds this question, including over the direction of US foreign policy, risks to European cohesion and slowing growth in China. However, two decades of revisionist behaviour by the authorities in Beijing show that China’s values and interests already conflict with transatlantic goals in trade, cyberspace, international development, security and human rights.
  • On trade, China pursues protectionist policies while engaging actively in intellectual property theft. China’s military modernization and its view of maritime law challenge the territorial status quo in East Asia and raise the risk of military crisis there. China lends unconditionally to countries that abuse human rights and are corrupt, undermining efforts by Western governments to promote good governance and human rights.
  • Defending liberal goals is complicated by asymmetric interests among the transatlantic partners, especially over security. China also uses ‘wedge’ strategies to pick off potential allies, thus diluting the power and will of any counterbalancing effort.
  • This briefing argues that China’s rise has worrying implications for the liberal international order. In response, the US should recognize its own strong interest in European unity, while Europeans must be ready to align more with the US (and East Asian allies) in order to temper Chinese behaviour.




hi

Why Britain’s 2019 Election Is Its Most Unpredictable in Recent History

7 November 2019

Professor Matthew Goodwin

Visiting Senior Fellow, Europe Programme
Leadership concerns and a collapse of traditional party loyalties make the December vote uncommonly volatile.

On 12 December, Britain will hold the most consequential election in its postwar history. The outcome of the election will influence not only the fate of Brexit but also the likelihood of a second referendum on EU membership, a second independence referendum in Scotland, the most economically radical Labour Party for a generation, Britain’s foreign and security policy and, ultimately, its position in the wider international order.

If you look only at the latest polls, then the outcome looks fairly certain. Ever since a majority of MPs voted to hold the election, the incumbent Conservative Party has averaged 38%, the opposition Labour Party 27%, the Liberal Democrats 16%, Brexit Party 10%, Greens 4% and Scottish National Party 3%. Prime Minister Boris Johnson and his party continue to average an 11-point lead which, if this holds until the election, would likely deliver a comfortable majority.

Johnson can also point to other favourable metrics. When voters are asked who would make the ‘best prime minister’, a clear plurality (43%) say Johnson while only a small minority (20%) choose the Labour Party leader, Jeremy Corbyn. Polls also suggest that, on the whole, Johnson is more trusted by voters than Corbyn to deal with Brexit, the economy and crime, while Jeremy Corbyn only tends to enjoy leads on health. All of this lends credence to the claim that Britain could be set for a Conservative majority and, in turn, the passing of a withdrawal agreement bill in early 2020.

But these polls also hide a lot of other shifts that are taking place and which, combined, make the 2019 general election unpredictable. One concerns leadership. While Boris Johnson enjoys stronger leadership ratings than Jeremy Corbyn, it should be remembered that what unites Britain’s current generation of party leaders is that they are all unpopular. Data compiled by Ipsos-MORI reveals that while Johnson has the lowest ratings of any new prime minister, Labour’s Jeremy Corbyn has the lowest ratings of any opposition leader since records began.

Another deeper shift is fragmentation. One irony of Britain’s Brexit moment is that ever since the country voted to leave the European Union its politics have looked more ‘European’. Over the past year, one of the world’s most stable two-party systems has imploded into a four-party race, with the anti-Brexit Liberal Democrats and Nigel Farage’s strongly Eurosceptic Brexit Party both presenting a serious challenge to the two mainstream parties.

In the latest polls, for example, Labour and the Conservatives are attracting only 61 per cent of the overall vote, well down on the 80 per cent they polled in 2017. Labour is weakened by the fact that it is only currently attracting 53 per cent of people who voted Labour at the last election, in 2017. A large number of these 2017 Labour voters, nearly one in four, have left for the Liberal Democrats, who are promising to revoke Article 50 and ‘cancel Brexit’. This divide in the Remain vote will produce unpredictable outcomes at the constituency level.

At the other end of the spectrum, the Conservatives are grappling with a similar but less severe threat. Nigel Farage and the Brexit Party are attracting around one in ten people who voted Conservative in 2017, which will make Boris Johnson’s task of capturing the crucial ‘Labour Leave’ seats harder. There is clear evidence that Johnson has been curbing Farage’s appeal, but it remains unclear how this rivalry on the right will play out from one seat to the next.

One clue as to what happens next can be found in those leadership ratings. While 80 per cent of Brexit Party voters back Johnson over Corbyn, only 25 per cent of Liberal Democrat voters back Corbyn over Johnson. Johnson may find it easier to consolidate the Leave vote than Corbyn will find the task of consolidating the Remain vote.

All of this reflects another reason why the election is unpredictable: volatility. This election is already Britain’s fifth nationwide election in only four years. After the 2015 general election, 2016 EU referendum, 2017 general election and 2019 European parliament elections, Britain’s political system and electorate have been in a state of almost continual flux. Along the way, a large number of voters have reassessed their loyalties.

As the British Election Study makes clear, the current rate of ‘vote-switching’ in British politics, where people switch their vote from one election to the next, is largely unprecedented in the post-war era. Across the three elections held in 2010, 2015 and 2017, a striking 49 per cent of people switched their vote.

This is not all about Brexit. Attachment to the main parties has been weakening since the 1960s. But Brexit is now accelerating this process as tribal identities as ‘Remainers’ or ‘Leavers’ cut across traditional party loyalties. All this volatility not only gives good reason to expect further shifts in support during the campaign but to also meet any confident predictions about the election result with a healthy dose of scepticism.




hi

Transatlantic Dialogue on China

A joint Chatham House-RUSI project that focuses on strengthening common understanding across the Atlantic and develop new ideas for how the US and Europe can better engage with and respond to China’s rise.

This will be done through examining transatlantic approaches and responses to China through the lens for four key themes (digital technology; trade and investment; governance of global commons; and climate change and the environment) that have been identified as crucial to developing effective policy responses and fostering collaboration.

The project will strengthen national, regional and international responses to the risks and opportunities posed by China’s changing role within the global economy and international rules-based order.

Department contact

Pepijn Bergsen

Research Fellow, Europe Programme
020 795 75748

More on Transatlantic Dialogue on China




hi

Another CDU Leadership Race Begins in Merkel’s Shadow

28 February 2020

Quentin Peel

Associate Fellow, Europe Programme
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.




hi

Structural and mutational analyses of the bifunctional arginine dihydrolase and ornithine cyclodeaminase AgrE from the cyanobacterium Anabaena [Enzymology]

In cyanobacteria, metabolic pathways that use the nitrogen-rich amino acid arginine play a pivotal role in nitrogen storage and mobilization. The N-terminal domains of two recently identified bacterial enzymes: ArgZ from Synechocystis and AgrE from Anabaena, have been found to contain an arginine dihydrolase. This enzyme provides catabolic activity that converts arginine to ornithine, resulting in concomitant release of CO2 and ammonia. In Synechocystis, the ArgZ-mediated ornithine–ammonia cycle plays a central role in nitrogen storage and remobilization. The C-terminal domain of AgrE contains an ornithine cyclodeaminase responsible for the formation of proline from ornithine and ammonia production, indicating that AgrE is a bifunctional enzyme catalyzing two sequential reactions in arginine catabolism. Here, the crystal structures of AgrE in three different ligation states revealed that it has a tetrameric conformation, possesses a binding site for the arginine dihydrolase substrate l-arginine and product l-ornithine, and contains a binding site for the coenzyme NAD(H) required for ornithine cyclodeaminase activity. Structure–function analyses indicated that the structure and catalytic mechanism of arginine dihydrolase in AgrE are highly homologous with those of a known bacterial arginine hydrolase. We found that in addition to other active-site residues, Asn-71 is essential for AgrE's dihydrolase activity. Further analysis suggested the presence of a passage for substrate channeling between the two distinct AgrE active sites, which are situated ∼45 Å apart. These results provide structural and functional insights into the bifunctional arginine dihydrolase–ornithine cyclodeaminase enzyme AgrE required for arginine catabolism in Anabaena.




hi

Processivity of dextransucrases synthesizing very-high-molar-mass dextran is mediated by sugar-binding pockets in domain V [Glycobiology and Extracellular Matrices]

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.




hi

The Escherichia coli cellulose synthase subunit G (BcsG) is a Zn2+-dependent phosphoethanolamine transferase [Glycobiology and Extracellular Matrices]

Bacterial biofilms are cellular communities that produce an adherent matrix. Exopolysaccharides are key structural components of this matrix and are required for the assembly and architecture of biofilms produced by a wide variety of microorganisms. The human bacterial pathogens Escherichia coli and Salmonella enterica produce a biofilm matrix composed primarily of the exopolysaccharide phosphoethanolamine (pEtN) cellulose. Once thought to be composed of only underivatized cellulose, the pEtN modification present in these matrices has been implicated in the overall architecture and integrity of the biofilm. However, an understanding of the mechanism underlying pEtN derivatization of the cellulose exopolysaccharide remains elusive. The bacterial cellulose synthase subunit G (BcsG) is a predicted inner membrane–localized metalloenzyme that has been proposed to catalyze the transfer of the pEtN group from membrane phospholipids to cellulose. Here we present evidence that the C-terminal domain of BcsG from E. coli (EcBcsGΔN) functions as a phosphoethanolamine transferase in vitro with substrate preference for cellulosic materials. Structural characterization of EcBcsGΔN revealed that it belongs to the alkaline phosphatase superfamily, contains a Zn2+ ion at its active center, and is structurally similar to characterized enzymes that confer colistin resistance in Gram-negative bacteria. Informed by our structural studies, we present a functional complementation experiment in E. coli AR3110, indicating that the activity of the BcsG C-terminal domain is essential for integrity of the pellicular biofilm. Furthermore, our results established a similar but distinct active-site architecture and catalytic mechanism shared between BcsG and the colistin resistance enzymes.




hi

Crystallographic and kinetic analyses of the FdsBG subcomplex of the cytosolic formate dehydrogenase FdsABG from Cupriavidus necator [Molecular Biophysics]

Formate oxidation to carbon dioxide is a key reaction in one-carbon compound metabolism, and its reverse reaction represents the first step in carbon assimilation in the acetogenic and methanogenic branches of many anaerobic organisms. The molybdenum-containing dehydrogenase FdsABG is a soluble NAD+-dependent formate dehydrogenase and a member of the NADH dehydrogenase superfamily. Here, we present the first structure of the FdsBG subcomplex of the cytosolic FdsABG formate dehydrogenase from the hydrogen-oxidizing bacterium Cupriavidus necator H16 both with and without bound NADH. The structures revealed that the two iron-sulfur clusters, Fe4S4 in FdsB and Fe2S2 in FdsG, are closer to the FMN than they are in other NADH dehydrogenases. Rapid kinetic studies and EPR measurements of rapid freeze-quenched samples of the NADH reduction of FdsBG identified a neutral flavin semiquinone, FMNH•, not previously observed to participate in NADH-mediated reduction of the FdsABG holoenzyme. We found that this semiquinone forms through the transfer of one electron from the fully reduced FMNH−, initially formed via NADH-mediated reduction, to the Fe2S2 cluster. This Fe2S2 cluster is not part of the on-path chain of iron-sulfur clusters connecting the FMN of FdsB with the active-site molybdenum center of FdsA. According to the NADH-bound structure, the nicotinamide ring stacks onto the re-face of the FMN. However, NADH binding significantly reduced the electron density for the isoalloxazine ring of FMN and induced a conformational change in residues of the FMN-binding pocket that display peptide-bond flipping upon NAD+ binding in proper NADH dehydrogenases.




hi

Thioredoxin regulates human mercaptopyruvate sulfurtransferase at physiologically-relevant concentrations [Enzymology]

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.




hi

The recalibration of Chinese assertiveness: China's responses to the Indo-Pacific challenge

8 January 2020 , Volume 96, Number 1

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.




hi

Non-traditional security cooperation between China and south-east Asia: implications for Indo-Pacific geopolitics

8 January 2020 , Volume 96, Number 1

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.




hi

Japan's ‘Indo-Pacific’ question: countering China or shaping a new regional order?

8 January 2020 , Volume 96, Number 1

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.




hi

Understanding the dynamics of the Indo-Pacific: US–China strategic competition, regional actors, and beyond

6 November 2019 , Volume 96, Number 1

The first issue of International Affairs in 2020 explores the geopolitics of the 'Indo-Pacific' region.

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.




hi

The Commonwealth Cyber Declaration: Achievements and Way Forward

Invitation Only Research Event

4 February 2020 - 9:15am to 5:30pm

Chatham House, London

In April 2018, the Commonwealth Heads of Government Meeting (CHOGM), held in London, saw the creation and the adoption of the Commonwealth Cyber Declaration. The declaration outlines the framework for a concerted effort to advance cybersecurity practices to promote a safe and prosperous cyberspace for Commonwealth citizens, businesses and societies. 

The conference will aim to provide an overview on the progress made on cybersecurity in the Commonwealth since the declaration was announced in 2018. In addition, it will examine future challenges and potential solutions going forward.

This conference is part of the International Security Programme's project on Implementing the Commonwealth Cybersecurity Agenda and will convene a range of senior Commonwealth representatives as well as a selection of civil society and industry stakeholders. This project aims to develop a pan-Commonwealth platform to take the Commonwealth Cyber Declaration forward by means of a holistic, inclusive and representative approach.

Please see below meeting summaries from previous events on Cybersecurity in the Commonwealth:  

Attendance at this event is by invitation only. 

Esther Naylor

Research Assistant, International Security Programme
+44 (0)20 7314 3628




hi

Unpacking the role of religion in political transnationalism: the case of the Shi'a Iraqi diaspora since 2003

4 March 2020 , Volume 96, Number 2

Oula Kadhum

This article explores the role of religion in political transnationalism using the case of the Shi'a Iraqi diaspora since 2003. The article focuses on three areas that capture important trends in Shi'a transnationalism and their implications for transnational Shi'a identity politics. These include Shi'a diasporic politics, transnational Shi'a civic activism, and the cultural production of Iraqi Shi'a identity through pilgrimages, rituals and new practices. It is argued that understanding Shi'a Islam and identity formation requires adopting a transnational lens. The evolution of Shi'a Islam is not only a result of the dictates of the Shi'a clerical centres, and how they influence Shi'a populations abroad, but also the transnational interrelationships and links to holy shrine cities, Shi'i national and international politics, humanitarianism and commemorations and rituals. The article demonstrates that Shi'a political transnationalism is unexceptional in that it echoes much of the literature on diasporic politics and development where diaspora involve themselves from afar in the politics and societies of their countries of origin. At the same time, it shows the exceptionalism of Shi'a diasporic movements, in that their motivations and mobilizations are contributing to the reification of sectarian geographical and social borders, creating a transnationalism that is defined by largely Shi'a networks, spaces, actors and causes. The case of Shi'a political transnationalism towards Iraq shows that this is increasing the distance between Shi'is and Iraq's other communities, simultaneously fragmenting Iraq's national unity while deepening Shi'a identity and politics both nationally and supra-nationally.




hi

The great Chinese surprise: the rupture with the United States is real and is happening

4 March 2020 , Volume 96, Number 2

Xiangfeng Yang

Ample evidence exists that China was caught off guard by the Trump administration's onslaught of punishing acts—the trade war being a prime, but far from the only, example. This article, in addition to contextualizing their earlier optimism about the relations with the United States under President Trump, examines why Chinese leaders and analysts were surprised by the turn of events. It argues that three main factors contributed to the lapse of judgment. First, Chinese officials and analysts grossly misunderstood Donald Trump the individual. By overemphasizing his pragmatism while downplaying his unpredictability, they ended up underprepared for the policies he unleashed. Second, some ingrained Chinese beliefs, manifested in the analogies of the pendulum swing and the ‘bickering couple’, as well as the narrative of the ‘ballast’, lulled officials and scholars into undue optimism about the stability of the broader relationship. Third, analytical and methodological problems as well as political considerations prevented them from fully grasping the strategic shift against China in the US.




hi

Children 'born of war': a role for fathers?

4 March 2020 , Volume 96, Number 2

Camile Oliviera, Erin Baines

In this article, we examine exceptional circumstances in which men who father children born as the result of conflict-related sexual violence assume full or partial responsibility for their child's well-being. Children ‘born of war’ are increasingly recognized as a particular victim group in relevant international policy frameworks. Their social status falls somewhere between the victimization of their mother and perpetration of their father. Given the circumstances of their birth, they often experience social rejection and loss of identity with a long-term impact on their well-being. Previous scholarship has primarily documented the challenges faced by their mothers as caregivers and as victims of wartime sexual violence. A discussion on fathers to children ‘born of war’ is absent, attributable not only to their perpetrator status, but also to the assumption that their identity is unknown or that a relationship between father and child is undesired. The article demonstrates this is not always the case. Based on research in northern Uganda between 2016 and 2019 which included interviews and focus group discussions with former male combatants in the rebel group the Lord's Resistance Army, we explore how some fathers seek to maintain a relationship with children born as the result of ‘forced marriage’ and assume partial or full responsibility for their well-being and care.




hi

Legal Provision for Crisis Preparedness: Foresight not Hindsight

21 April 2020

Dr Patricia Lewis

Research Director, Conflict, Science & Transformation; Director, International Security Programme
COVID-19 is proving to be a grave threat to humanity. But this is not a one-off, there will be future crises, and we can be better prepared to mitigate them.

2020-04-21-Nurse-COVID-Test

Examining a patient while testing for COVID-19 at the Velocity Urgent Care in Woodbridge, Virginia. Photo by Chip Somodevilla/Getty Images.

A controversial debate during COVID-19 is the state of readiness within governments and health systems for a pandemic, with lines of the debate drawn on the issues of testing provision, personal protective equipment (PPE), and the speed of decision-making.

President Macron in a speech to the nation admitted French medical workers did not have enough PPE and that mistakes had been made: ‘Were we prepared for this crisis? We have to say that no, we weren’t, but we have to admit our errors … and we will learn from this’.

In reality few governments were fully prepared. In years to come, all will ask: ‘how could we have been better prepared, what did we do wrong, and what can we learn?’. But after every crisis, governments ask these same questions.

Most countries have put in place national risk assessments and established processes and systems to monitor and stress-test crisis-preparedness. So why have some countries been seemingly better prepared?

Comparing different approaches

Some have had more time and been able to watch the spread of the disease and learn from those countries that had it first. Others have taken their own routes, and there will be much to learn from comparing these different approaches in the longer run.

Governments in Asia have been strongly influenced by the experience of the SARS epidemic in 2002-3 and - South Korea in particular - the MERS-CoV outbreak in 2015 which was the largest outside the Middle East. Several carried out preparatory work in terms of risk assessment, preparedness measures and resilience planning for a wide range of threats.

Case Study of Preparedness: South Korea

By 2007, South Korea had established the Division of Public Health Crisis Response in Korea Centers for Disease Control and Prevention (KCDC) and, in 2016, the KCDC Center for Public Health Emergency Preparedness and Response had established a round-the-clock Emergency Operations Center with rapid response teams.

KCDC is responsible for the distribution of antiviral stockpiles to 16 cities and provinces that are required by law to hold and manage antiviral stockpiles.

And, at the international level, there are frameworks for preparedness for pandemics. The International Health Regulations (IHR) - adopted at the 2005 World Health Assembly and binding on member states - require countries to report certain disease outbreaks and public health events to the World Health Organization (WHO) and ‘prevent, protect against, control and provide a public health response to the international spread of disease in ways that are commensurate with and restricted to public health risks, and which avoid unnecessary interference with international traffic and trade’.

Under IHR, governments committed to a programme of building core capacities including coordination, surveillance, response and preparedness. The UN Sendai Framework for Disaster Risk highlights disaster preparedness for effective response as one of its main purposes and has already incorporated these measures into the Sustainable Development Goals (SDGs) and other Agenda 2030 initiatives. UN Secretary-General António Guterres has said COVID-19 ‘poses a significant threat to the maintenance of international peace and security’ and that ‘a signal of unity and resolve from the Council would count for a lot at this anxious time’.

Case Study of Preparedness: United States

The National Institutes of Health (NIH) and the Center for Disease Control (CDC) established PERRC – the Preparedness for Emergency Response Research Centers - as a requirement of the 2006 Pandemic and All-Hazards Preparedness Act, which required research to ‘improve federal, state, local, and tribal public health preparedness and response systems’.

The 2006 Act has since been supplanted by the 2019 Pandemic and All-Hazards Preparedness and Advancing Innovation Act. This created the post of Assistant Secretary for Preparedness and Response (ASPR) in the Department for Health and Human Services (HHS) and authorised the development and acquisitions of medical countermeasures and a quadrennial National Health Security Strategy.

The 2019 Act also set in place a number of measures including the requirement for the US government to re-evaluate several important metrics of the Public Health Emergency Preparedness cooperative agreement and the Hospital Preparedness Program, and a requirement for a report on the states of preparedness and response in US healthcare facilities.

This pandemic looks set to continue to be a grave threat to humanity. But there will also be future pandemics – whether another type of coronavirus or a new influenza virus – and our species will be threatened again, we just don’t know when.

Other disasters too will befall us – we already see the impacts of climate change arriving on our doorsteps characterised by increased numbers and intensity of floods, hurricanes, fires, crop failure and other manifestations of a warming, increasingly turbulent atmosphere and we will continue to suffer major volcanic eruptions, earthquakes and tsunamis. All high impact, unknown probability events.

Preparedness for an unknown future is expensive and requires a great deal of effort for events that may not happen within the preparers’ lifetimes. It is hard to imagine now, but people will forget this crisis, and revert to their imagined projections of the future where crises don’t occur, and progress follows progress. But history shows us otherwise.

Preparations for future crises always fall prey to financial cuts and austerity measures in lean times unless there is a mechanism to prevent that. Cost-benefit analyses will understandably tend to prioritise the urgent over the long-term. So governments should put in place legislation – or strengthen existing legislation – now to ensure their countries are as prepared as possible for whatever crisis is coming.

Such a legal requirement would require governments to report back to parliament every year on the state of their national preparations detailing such measures as:

  • The exact levels of stocks of essential materials (including medical equipment)
  • The ability of hospitals to cope with large influx of patients
  • How many drills, exercises and simulations had been organised – and their findings
  • What was being done to implement lessons learned & improve preparedness

In addition, further actions should be taken:

  • Parliamentary committees such as the UK Joint Committee on the National Security Strategy should scrutinise the government’s readiness for the potential threats outlined in the National Risk register for Civil Emergencies in-depth on an annual basis.
  • Parliamentarians, including ministers, with responsibility for national security and resilience should participate in drills, table-top exercises and simulations to see for themselves the problems inherent with dealing with crises.
  • All governments should have a minister (or equivalent) with the sole responsibility for national crisis preparedness and resilience. The Minister would be empowered to liaise internationally and coordinate local responses such as local resilience groups.
  • There should be ring-fenced budget lines in annual budgets specifically for preparedness and resilience measures, annually reported on and assessed by parliaments as part of the due diligence process.

And at the international level:

  • The UN Security Council should establish a Crisis Preparedness Committee to bolster the ability of United Nations Member States to respond to international crisis such as pandemics, within their borders and across regions. The Committee would function in a similar fashion as the Counter Terrorism Committee that was established following the 9/11 terrorist attacks in the United States.
  • States should present reports on their level of preparedness to the UN Security Council. The Crisis Preparedness Committee could establish a group of experts who would conduct expert assessments of each member state’s risks and preparedness and facilitate technical assistance as required.
  • Regional bodies such as the OSCE, ASEAN and ARF, the AU, the OAS, the PIF etc could also request national reports on crisis preparedness for discussion and cooperation at the regional level.

COVID-19 has been referred to as the 9/11 of crisis preparedness and response. Just as that shocking terrorist attack shifted the world and created a series of measures to address terrorism, we now recognise our security frameworks need far more emphasis on being prepared and being resilient. Whatever has been done in the past, it is clear that was nowhere near enough and that has to change.

Case Study of Preparedness: The UK

The National Risk Register was first published in 2008 as part of the undertakings laid out in the National Security Strategy (the UK also published the Biological Security Strategy in July 2018). Now entitled the National Risk Register for Civil Emergencies it has been updated regularly to analyse the risks of major emergencies that could affect the UK in the next five years and provide resilience advice and guidance.

The latest edition - produced in 2017 when the UK had a Minister for Government Resilience and Efficiency - placed the risk of a pandemic influenza in the ‘highly likely and most severe’ category. It stood out from all the other identified risks, whereas an emerging disease (such as COVID-19) was identified as ‘highly likely but with moderate impact’.

However, much preparatory work for an influenza pandemic is the same as for COVID-19, particularly in prepositioning large stocks of PPE, readiness within large hospitals, and the creation of new hospitals and facilities.

One key issue is that the 2017 NHS Operating Framework for Managing the Response to Pandemic Influenza was dependent on pre-positioned ’just in case’ stockpiles of PPE. But as it became clear the PPE stocks were not adequate for the pandemic, it was reported that recommendations about the stockpile by NERVTAG (the New and Emerging Respiratory Virus Threats Advisory Group which advises the government on the threat posed by new and emerging respiratory viruses) had been subjected to an ‘economic assessment’ and decisions reversed on, for example, eye protection.

The UK chief medical officer Dame Sally Davies, when speaking at the World Health Organization about Operation Cygnus – a 2016 three-day exercise on a flu pandemic in the UK – reportedly said the UK was not ready for a severe flu attack and ‘a lot of things need improving’.

Aware of the significance of the situation, the UK Parliamentary Joint Committee on the National Security Strategy launched an inquiry in 2019 on ‘Biosecurity and human health: preparing for emerging infectious diseases and bioweapons’ which intended to coordinate a cross-government approach to biosecurity threats. But the inquiry had to postpone its oral hearings scheduled for late October 2019 and, because of the general election in December 2019, the committee was obliged to close the inquiry.




hi

Webinar: Can Responsible Behaviour in Cyberspace Be Achieved?

Members Event Webinar

26 May 2020 - 5:00pm to 6:00pm
Add to Calendar

Online

Carmen Gonsalves, Head, International Cyber Policy, Ministry of Foreign Affairs, Netherlands
Suzanne Spaulding, Senior Adviser for Homeland Security, Center for Strategic and International Studies
Chair: Joyce Hakmeh, Senior Research Fellow, International Security Programme and Co-Editor, Journal of Cyber Policy, Chatham House

Over the past couple of decades, cyberspace has evolved to become a truly global digital communication space. Managed by a multitude of state and non-state actors, it has enabled a huge range of positive innovations and developments. However, it has also become an arena of intense international competition and rivalry – a reflection of its increasing economic and political importance and broader geopolitical tensions. Despite a number of efforts and some progress in the United Nations and other forums, there are still disagreements on key issues between major powers on how to achieve responsible behaviour in cyberspace.

In light of this, the panel will explore how state and non-state actors can work together to encourage responsible behaviour in cyberspace. What challenges do various actors face in implementing agreed upon norms and principles? Is the existing global model for reaching an agreement a non-starter? What are the remaining challenges around attribution, accountability and enforcement? And what is the role for civil society, the private sector and NGOs in this debate?

This event is for Chatham House members only. Not a member? Find out more.




hi

It's a man's world: carnal spectatorship and dissonant masculinities in Islamic State videos

7 May 2020 , Volume 96, Number 3

Manni Crone

Islamic State videos have often been associated with savage violence and beheadings. An in-depth scrutiny however reveals another striking feature: that female bodies are absent, blurred or mute. Examining a few Islamic State videos in depth, the article suggests that the invisibility of women in tandem with the ostentatious visibility of male bodies enable gendered and embodied spectators to indulge in homoerotic as well as heterosexual imaginaries. In contrast to studies on visual security and online radicalization which assert that images affect an audience, this article focuses on the interaction between video and audience and argues that spectators are not only rational and emotional but embodied and gendered as well. Islamic State videos do not only attract western foreign fighters through religious–ideological rhetoric or emotional impact but also through gendered forms of pleasure and desire that enable carnal imagination and identification. The article probes the analytical purchase of carnal aesthetics and spectatorship.




hi

Politics, policy-making and the presence of images of suffering children

7 May 2020 , Volume 96, Number 3

Helen Berents

In 2017 Trump expressed pity for the ‘beautiful babies’ killed in a gas attack on Khan Shaykhun in Syria before launching airstrikes against President Assad's regime. Images of suffering children in world politics are often used as a synecdoche for a broader conflict or disaster. Injured, suffering, or dead; the ways in which images of children circulate in global public discourse must be critically examined to uncover the assumptions that operate in these environments. This article explores reactions to images of children by representatives and leaders of states to trace the interconnected affective and political dimensions of these images. In contrast to attending to the expected empathetic responses prompted by images of children, this article particularly focuses on when such images prompt bellicose foreign policy decision-making. In doing this, the article forwards a way of thinking about images as contentious affective objects in international relations. The ways in which images of children's bodies and suffering are strategically deployed by politicians deserves closer scrutiny to uncover the visual politics of childhood inherent in these moments of international politics and policy-making.




hi

Soundscapes of war: the audio-visual performance of war by Shi'a militias in Iraq and Syria

7 May 2020 , Volume 96, Number 3

Helle Malmvig

This article sets out to bring sound and music to the field of visual studies in International Relations. It argues that IR largely has approached the visual field as if it was without sound; neglecting how audial landscapes frame and direct our interpretation of moving imagery. Sound and music contribute to making imagery intelligible to us, we ‘hear the pictures’ often without noticing. The audial can for instance articulate a visual absence, or blast visual signs, bring out certain emotional stages or subjects’ inner life. Audial frames steer us in distinct directions, they can mute the cries of the wounded in war, or amplify the sounds of joy of soldiers shooting in the air. To bring the audial and the visual analytically and empirically together, the article therefore proposes four key analytical themes: 1) the audial–visual frame, 2) point of view/point of audition, 3) modes of audio-visual synchronization and 4) aesthetics moods. These are applied to a study of ‘war music videos’ in Iraq and Syria made and circulated by Shi'a militias currently fighting there. Such war music videos, it is suggested, are not just artefacts of popular culture, but have become integral parts of how warfare is practiced today, and one that is shared by soldiers in the US and Europe. War music videos are performing war, just as they shape how war is known by spectators and participants alike.




hi

China and Russia in R2P debates at the UN Security Council

7 May 2020 , Volume 96, Number 3

Zheng Chen and Hang Yin

While China and Russia's general policies towards the Responsibility to Protect (R2P) are similar, the two reveal nuanced differences in addressing specific emergencies. Both express support for the first two pillars of R2P while resisting coercive intervention under its aegis, as they share anxieties of domestic political security and concerns about their international image. Nonetheless, addressing cases like the Syrian crisis, Russian statements are more assertive and even aggressive while Chinese ones are usually vague and reactive. This article highlights the two states’ different tones through computer-assisted text analyses. It argues that diplomatic styles reflect Russian and Chinese perceptions of their own place in the evolving international order. Experiences in past decades create divergent reference points and status prospects for them, which leads to their different strategies in signalling Great Power status. As Beijing is optimistic about its status-rising prospects, it exercises more self-restraint in order to avoid external containments and is reluctant to act as an independent ‘spoiler’. Meanwhile, Moscow interprets its Great Power status more from a frame of ‘loss’ and therefore is inclined to adopt a sterner approach to signal its status. Although their policies complement each other on many occasions, there is nothing akin to a Sino–Russian ‘bloc’.




hi

A Transatlantic Partnership for WTO Reform in the Age of Coronavirus

Webinar Research Event

28 April 2020 - 2:00pm to 3:00pm

Event participants

Ignacio Garcia Bercero, Director, Directorate General for Trade of the European Commission; European Union Visiting Fellow, Oxford University
Jennifer Hillman, Senior Fellow for Trade and International Political Economy, Council on Foreign Relations; Member, WTO Appellate Body, 2007 - 11
Chair: Marianne Schneider-Petsinger, Senior Research Fellow, US and Americas Programme, Chatham House

Global trade and the WTO – which has been at the heart of the rules-based international trade system since its creation in 1995 – faced a critical moment even before COVID-19. The Appellate Body’s demise in December 2019 led to a renewed focus on the future of the WTO. But the challenges facing the WTO run deeper than that – the organization has lost relevance as a negotiation forum, resulting in the global trade rules not having kept pace with changes in technology and the rise of China. While the WTO provides a forum for international cooperation to address the trade fallout from COVID-19, what implications will the pandemic have for the long-term reform of the global trade system?

Both the US and EU have proposed various WTO reform strategies and taken steps towards collaboration, but is a transatlantic partnership for WTO reform feasible? Do the US and EU believe that a rules-based international trade system is in their interest – especially in light of COVID-19? What are the biggest issues dividing the US and EU on reforming the WTO, and is there a common assessment of the key problems? What steps can the US and EU take to address the dispute settlement function of the WTO and to modernize the trade rules? Are there broader issues, such as environmental and social sustainability, that should be included in a transatlantic agenda for WTO reform?

This event is  part of the Chatham House Global Trade Policy Forum and will take place virtually only.

We would like to take this opportunity to thank founding partner AIG and supporting partners Clifford Chance LLP, Diageo plc, and EY for their generous support of the Chatham House Global Trade Policy Forum.




hi

Webinar: Make or Break: China and the Geopolitical Impacts of COVID-19

Research Event

28 April 2020 - 12:00pm to 12:45pm

Event participants

Yu Jie, Senior Research Fellow on China, Asia-Pacific Programme, Chatham House
Kerry Brown, Associate Fellow, Asia-Pacific Programme, Chatham House; Professor of Chinese Studies and Director of Lau China Institute, King’s College London

The COVID-19 crisis has accelerated geopolitical tensions that, in part, have arisen from US-China tensions. At a time when the world needs strong and collective leadership to fight the coronavirus, both countries have been locked in a battle of words characterized by escalating hostility, polarizing narratives, blame and misinformation. Caught in the crossfire, many people of Chinese descent across differing countries have reported an increase in xenophobic attacks.

Middle powers such as the UK and Australia have swerved between recognition of the global collaboration needed to solve this pandemic and calls for China to be held ‘accountable’ for its initial response. Others such, as France and Japan, have been trying to foster international cooperation. 

Against this context, speakers will discuss China’s response to the crisis, including the initial delay and Beijing’s later containment strategies. How do we best assess the delay amidst all the heated rhetoric? What was the response of people within China to the measures? Does COVID-19 mark a point of no return for US-China relations? How might this impact on relations between US allies and China? And what kind of China will emerge from this current crisis?

Lucy Ridout

Programme Administrator, Asia-Pacific Programme
+44 (0) 207 314 2761




hi

Virtual Roundtable: As COVID-19 Hits the Developing World, Where is the American-led Global Response?

Research Event

9 June 2020 - 2:00pm to 3:00pm
Add to Calendar

Lord Mark Malloch-Brown, Chairman, SGO; Former Deputy Secretary-General and Chief of Staff, United Nations
Dr Elizabeth Cousens, President and CEO, United Nations Foundation
Ambassador Nicholas Burns, Roy and Barbara Goodman Family Professor of the Practice of Diplomacy and International Relations at the Harvard Kennedy School; US Under Secretary of State for Political Affairs, 2005 – 2008
Chair: Dr Leslie Vinjamuri, Director, US and the 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.

This event will take place from 14:00 – 15:00 BST.

US and Americas Programme

Department/project




hi

Webinar: Can Responsible Behaviour in Cyberspace Be Achieved?

Members Event Webinar

26 May 2020 - 5:00pm to 6:00pm
Add to Calendar

Online

Carmen Gonsalves, Head, International Cyber Policy, Ministry of Foreign Affairs, Netherlands
Suzanne Spaulding, Senior Adviser for Homeland Security, Center for Strategic and International Studies
Chair: Joyce Hakmeh, Senior Research Fellow, International Security Programme and Co-Editor, Journal of Cyber Policy, Chatham House

Over the past couple of decades, cyberspace has evolved to become a truly global digital communication space. Managed by a multitude of state and non-state actors, it has enabled a huge range of positive innovations and developments. However, it has also become an arena of intense international competition and rivalry – a reflection of its increasing economic and political importance and broader geopolitical tensions. Despite a number of efforts and some progress in the United Nations and other forums, there are still disagreements on key issues between major powers on how to achieve responsible behaviour in cyberspace.

In light of this, the panel will explore how state and non-state actors can work together to encourage responsible behaviour in cyberspace. What challenges do various actors face in implementing agreed upon norms and principles? Is the existing global model for reaching an agreement a non-starter? What are the remaining challenges around attribution, accountability and enforcement? And what is the role for civil society, the private sector and NGOs in this debate?

This event is for Chatham House members only. Not a member? Find out more.




hi

Webinar: Director's Briefing – National Leadership in Times of Crisis

Corporate Members Event Webinar Partners and Major Corporates

14 May 2020 - 6:00pm to 7:00pm
Add to Calendar

Online

Janet Napolitano, President, University of California; US Secretary of Homeland Security (2009-13)

Chair: Dr Robin Niblett, Director and Chief Executive, Chatham House

Across the globe, leaders on the local, national and international levels are grappling with the impacts of COVID-19 on their communities and the economy. But the coronavirus pandemic is just one of several existential crises the world is currently facing. Climate change, political instability and growing tensions with China and Russia, along with a lack of strong global leadership, has made it more difficult for individual nations to respond and coalesce in times of crisis.

This discussion will explore how leaders at all levels can best negotiate both the practical issues and the larger questions associated with these ‘grand challenges’. How is current US foreign policy affecting our collective ability to respond to issues such as pandemics or climate change? Has the COVID-19 crisis cemented the US retreat from global leadership and if so, who might step into the breach? How do we maintain momentum on other issues in the midst of a public health disaster of this magnitude? And what is the role of the business community, higher education institutions and other sectors in responding to these crises and shaping future public policy?

This event is only open to Major Corporate Member and Partner organizations and selected giving circles of Chatham House. If you'd like to attend, please RSVP to lbedford@chathamhouse.org.




hi

Nowhere to Call Home: Ethnic Minorities in China

Members Event

18 February 2015 - 6:00pm to 7:15pm

Chatham House, London

Event participants

Jocelyn Ford, Journalist and Filmmaker, Nowhere to Call Home: A Tibetan in Beijing
Dr Reza Hasmath, Lecturer in Chinese Politics, University of Oxford
Chair: Rob Gifford, Correspondent, The Economist 

Jocelyn Ford will share her experiences and insights from documenting the struggles of a widowed Tibetan facing ethnic discrimination in Beijing and gender discrimination in her village. The panel will then have a wider discussion about national identity and the issues facing ethnic minorities in China.  

This discussion coincides with the UK screening of Nowhere to Call Home: A Tibetan in Beijing and will include clips from the film.




hi

The Road to Gender Equality: Achievements and Challenges in China

Invitation Only Research Event

23 May 2016 - 1:00pm to 3:00pm

Beijing, China

Following 21 years since the adoption of the Beijing declaration by 189 states, China has the opportunity to lead the way in prioritizing gender-inclusive growth policies on the G20 agenda, as it is hosting the G20 this year.

This roundtable will examine specific challenges in China, a country with a high heterogeneity in the labour force and among its population. The event will bring together representatives of government, business and civil society to continue the dialogue that Chatham House started one year ago in Beijing. Taking stock of the progress achieved so far, the participants will analyse what type of recommendations can have a positive impact in both rural and high- density populated areas.

Attendance at this event is by invitation only.

The Chatham House Rule 

To enable as open a debate as possible, this event will be held under the Chatham House Rule. 

Event attributes

Chatham House Rule

Michele Bazzano

Research Assistant, International Economics
+44 (0)20 7314 3684




hi

Syria: Destruction of Civil Society Means Dictatorship, Extremism and Displacement

7 October 2016

Rana Marcel Khalaf

Former Academy Associate
The void in governance in Syria caused by the conflict has enabled a previously oppressed civil society to rise. Now this new society is under threat. Sustained commitment from the international community is required.

2016-10-07-white-helmets-syria2.jpg

Syrian civil defence volunteers, known as the White Helmets, search amid the rubble of destroyed buildings following an air strike on the rebel-held neighbourhood of Aleppo, on October 4, 2016. Photo: Getty Images.

The void in governance created by the ongoing Syrian conflict has been capitalized upon by warlords, militias and extremist groups to expand and consolidate their power – but has also helped to generate activism, with new leaders born as a reaction to authoritarian governance and conflict limitations.

As public social services have been taken over as war tools, local coordination committees, local councils, humanitarian support groups, citizen journalist networks, women’s groups, and more, have mushroomed across all of Syria. But this new civil society continues to be threatened by many challenges.

It remains hindered by structural weakness and limited capacity - largely as a result of the legacy of Ba’athist policies, which did not allow civil society to exist in the so-called Damascus Spring, but only under the umbrella of the Government, First Lady Asma al-Assad and business NGOs (GoNGOs, FLNGOs and BoNGOs). Beyond this, civil society was limited to purely charitable and religious causes, known as “moujtamaa ahli”.

In addition, Syrian civil society is often a victim of counter-terrorism legislation, with laws and regulations across many countries and institutions prohibiting Syrians from registering an organization and opening bank accounts.  This makes it difficult to secure financial support in an environment where funding has already been dwindling due to a “Syria fatigue” among potential donors, and where any money available is mainly directed at large, often international, NGOs.

Trust, hope and legitimacy

To reach funds, many organizations have to submit to this “NGOization” process. But even this rarely allows for civil society to foster its own interests through core funding. Civil society in Syria is treated more as a “project” with strict indicators, deals and deadlines, when working under conflict necessitates building relationships of trust with a community over time and often has to cover the direct needs on the ground to gain local legitimacy and increase effectiveness. Trust, hope and legitimacy are not aspects you can report against or cover in a sophisticated proposal.

But despite such obstacles, activists and civil society groups continue to volunteer for various causes, ensuring many have not had to seek refuge elsewhere. And their work has included challenging authoritarian and extremist governance.

In Aleppo in 2014, it was civil society with the support of a military faction of Jaish Al Mujahideen that helped expel ISIS. Local councils have since been providing services ranging from humanitarian aid and garbage collection to re-establishing order and resolving local conflicts, thus challenging the legitimacy of jihadist institutions.

NGOs such as the Civil Defense Forces (known as the White Helmets) continually risk their lives to save others by rescuing people from bombed out buildings. On September 19, when a UN sanctioned aid convoy was attacked in Aleppo – reportedly by Russian aircraft – it was the White Helmets that responded, before then coming under attack themselves.

Human rights activists, meanwhile, persist in documenting human rights abuses in the hope that the perpetrators will eventually be held accountable.

However, a Syrian civil society tragedy is unfolding as their work is struggling to survive. To give but one example, Kesh Malek, one of the biggest groups running home-based schooling for children in Aleppo, has already had to close some of its schools.

Lacking international protection, the fate of these children in relation to arms and radicalization is all the more alarming.  Several local councils have also been much weakened, especially vis-à-vis warlords, authoritarian and/or extremists actors.

At its best, the current bombing campaign serves to kill any potential alternatives to an authoritarian regime, and only boosts human suffering, radicalization and displacement.

If this situation is to be reversed, international actors need to ensure security at the local Syrian level, showing that Syrian security is as important as that of Europe.

This means financial security through a deeper and more sustainable capacity building and funding to civil society, and it means protecting civilians and civil society groups though the creation of a safe haven.

To comment on this article, please contact Chatham House Feedback




hi

History for Fantasy Writers: Do You Have a Moment?

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.



  • History
  • history for fantasy writers
  • how time was perceived and measured

hi

History for Fantasy Writers: Bank on It

Banks appear in a number of fantasy stories. George Martin’s Iron Bank is probably the best known, but banks and banking families can be found all around the fantasy landscape, especially in modern works. For writers considering including banks and bankers in their own stories, knowing something of the history can help add detail and color.

Money Changers

Europe in the High Middle Ages, say around 1100, had a bewildering variety of coinage (see my article on medieval money), a crazy cobweb of overlapping public authority, and an unreliable network of roads. Banking arose in response to the need of merchants to conduct large-scale business at a distance in that environment.

As you might guess, with so many different coins, knowing how to convert from one currency to another was a fairly technical business. That business was handled by a money changer. In Florence and other north Italian towns, the money changers set up shop at markets and near merchant establishments—any place where there was plenty of commercial traffic. The benches they sat on are called banca in Italian. That’s where we get the term bank.

Money changers knew more than just how to convert currencies.

Continue reading History for Fantasy Writers: Bank on It at Mythic Scribes.



  • History
  • history for fantasy writers

hi

Cytochrome P450 and arachidonic acid bioactivation: molecular and functional properties of the arachidonate monooxygenase

Jorge H. Capdevila
Feb 1, 2000; 41:163-181
Reviews




hi

Normal high density lipoprotein inhibits three steps in the formation of mildly oxidized low density lipoprotein: steps 2 and 3

Mohamad Navab
Sep 1, 2000; 41:1495-1508
Articles




hi

Normal high density lipoprotein inhibits three steps in the formation of mildly oxidized low density lipoprotein: step 1

Mohamad Navab
Sep 1, 2000; 41:1481-1494
Articles




hi

Lipid extraction by methyl-tert-butyl ether for high-throughput lipidomics

Vitali Matyash
May 1, 2008; 49:1137-1146
Methods




hi

High density lipoprotein metabolism

S Eisenberg
Oct 1, 1984; 25:1017-1058
Reviews




hi

The amphipathic helix in the exchangeable apolipoproteins: a review of secondary structure and function

JP Segrest
Feb 1, 1992; 33:141-166
Reviews




hi

The plasma lecithin:cholesterol acyltransferase reaction

John A. Glomset
Mar 1, 1968; 9:155-167
Reviews