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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.




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Phosphoproteomic characterization of the signaling network resulting from activation of the chemokine receptor CCR2 [Genomics and Proteomics]

Leukocyte recruitment is a universal feature of tissue inflammation and regulated by the interactions of chemokines with their G protein–coupled receptors. Activation of CC chemokine receptor 2 (CCR2) by its cognate chemokine ligands, including CC chemokine ligand 2 (CCL2), plays a central role in recruitment of monocytes in several inflammatory diseases. In this study, we used phosphoproteomics to conduct an unbiased characterization of the signaling network resulting from CCL2 activation of CCR2. Using data-independent acquisition MS analysis, we quantified both the proteome and phosphoproteome in FlpIn-HEK293T cells stably expressing CCR2 at six time points after activation with CCL2. Differential expression analysis identified 699 significantly regulated phosphorylation sites on 441 proteins. As expected, many of these proteins are known to participate in canonical signal transduction pathways and in the regulation of actin cytoskeleton dynamics, including numerous guanine nucleotide exchange factors and GTPase-activating proteins. Moreover, we identified regulated phosphorylation sites in numerous proteins that function in the nucleus, including several constituents of the nuclear pore complex. The results of this study provide an unprecedented level of detail of CCR2 signaling and identify potential targets for regulation of CCR2 function.




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Inflammatory and mitogenic signals drive interleukin 23 subunit alpha (IL23A) secretion independent of IL12B in intestinal epithelial cells [Signal Transduction]

The heterodimeric cytokine interleukin-23 (IL-23 or IL23A/IL12B) is produced by dendritic cells and macrophages and promotes the proinflammatory and regenerative activities of T helper 17 (Th17) and innate lymphoid cells. A recent study has reported that IL-23 is also secreted by lung adenoma cells and generates an inflammatory and immune-suppressed stroma. Here, we observed that proinflammatory tumor necrosis factor (TNF)/NF-κB and mitogen-activated protein kinase (MAPK) signaling strongly induce IL23A expression in intestinal epithelial cells. Moreover, we identified a strong crosstalk between the NF-κB and MAPK/ERK kinase (MEK) pathways, involving the formation of a transcriptional enhancer complex consisting of proto-oncogene c-Jun (c-Jun), RELA proto-oncogene NF-κB subunit (RelA), RUNX family transcription factor 1 (RUNX1), and RUNX3. Collectively, these proteins induced IL23A secretion, confirmed by immunoprecipitation of endogenous IL23A from activated human colorectal cancer (CRC) cell culture supernatants. Interestingly, IL23A was likely secreted in a noncanonical form, as it was not detected by an ELISA specific for heterodimeric IL-23 likely because IL12B expression is absent in CRC cells. Given recent evidence that IL23A promotes tumor formation, we evaluated the efficacy of MAPK/NF-κB inhibitors in attenuating IL23A expression and found that the MEK inhibitor trametinib and BAY 11–7082 (an IKKα/IκB inhibitor) effectively inhibited IL23A in a subset of human CRC lines with mutant KRAS or BRAFV600E mutations. Together, these results indicate that proinflammatory and mitogenic signals dynamically regulate IL23A in epithelial cells. They further reveal its secretion in a noncanonical form independent of IL12B and that small-molecule inhibitors can attenuate IL23A secretion.




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Five Foreign Policy Questions for the UK’s Next Prime Minister

18 June 2019

Thomas Raines

Director, Europe Programme
Even if most don’t get to vote in the Conservative leadership election, the public deserves serious answers on the foreign policy plans of those who want to lead the country.

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10 Downing Street. Photo: Getty Images.

In a month’s time, the UK will have a new prime minister. The campaign has been dominated by candidates’ views on how to deliver Britain’s withdrawal from the EU by October, alongside some discussion of domestic issues.

But relatively little has been said about international affairs, despite the fact that foreign policy questions are becoming a more partisan issue and Britain is facing crucial questions around Brexit and the wider international context. These will be waiting for whoever finds themselves in Number 10 on 22 July. 

1. How can Britain influence Europe from outside the EU?

Theresa May was fond of saying that Britain is leaving the EU but not leaving Europe. Britain cannot change its geography. It will continue to share many strategic and security interests with the rest of the continent, but it will be outside of Europe’s central political and economic project. A new PM will not only have to negotiate Britain’s new relationship with the EU, but also think about how to influence it as a third country.

An aspect of this will be finding a new way to work with the EU on foreign, security and defence policy that meets the need for autonomy on both sides. How deep this relationship is or how institutionalized it will be is yet to be negotiated and can be shaped by the next PM.

The UK needs to decide how ambitiously it wants to engage with the new defence agenda in the EU (particularly its industrial components), and how to balance these with key bilateral relationships like France and Germany. Amid uncertainty about American security guarantees and Russian aggression, the next PM must also consider what Britain’s security role in Europe should be and NATO’s place within that.

Beyond conventional foreign policy issues, Britain is also going to be heavily shaped and influenced by the rule-making power of the EU, and how the world’s largest market regulates itself, from energy to financial services, consumer products and the environment.

The UK will need a strategy to influence the EU from the outside – something Swiss, Norwegians and Americans will acknowledge is no easy feat. This could include significantly increasing its diplomatic footprint across Europe, working closely with the UK’s private and non-profit sectors, utilizing Britain’s technical expertise in areas like sanctions, and creating new ad hoc groupings to share perspectives and ideas, building on examples like the Northern Future Forum

2. Should Britain do business with President Trump?

President Trump represents a fundamental challenge to Britain: an American president whose belligerent unilateralism runs counter to many of Britain’s foreign policy objectives. His frequent and often shameless diplomatic faux pas – from proposing Nigel Farage be the British ambassador to his dog-whistle attacks on the mayor of London – are compounded by real differences of substance on issues like trade, climate change and nuclear non-proliferation.

A new prime minister must decide how to manage relations with the US administration, whether to challenge or condemn a US president when he acts against Britain’s interests, or use flattery or quieter diplomacy to seek to influence him. Theresa May’s strategy of staying politically close to the president and playing to his ego has yielded little in policy terms, though other world leaders have fared little better.

A new PM will face some uncomfortable choices. Will they continue to defend the Iran nuclear deal alongside European allies while the US continues to undermine it? Do they believe a trade deal with America is desirable or achievable with the current administration, and what are they willing to sacrifice to achieve it? Is the American security guarantee for Europe secure with Donald Trump as president? Judgements on these questions should inform Britain's wider strategy, and its objectives for a future relationship with the European Union.

3. Should Britain prioritize economics or security in its relations with China?

Britain faces its own version of the challenge that many countries face – how to balance the economic and investment benefits of a positive relationship with China with concerns about repressive domestic politics and a more assertive Chinese role regionally and globally. This tension has become more acute for two reasons.

First, the economic dislocation of leaving the EU may create a greater reliance on Chinese trade and investment. China is already a major investor in the UK. If Brexit proves to be disorderly, Britain’s need may be all the greater (though China faces economic headwinds as well). Some in Brussels even fear that the economic difficulties of Brexit may make the UK a soft touch for emerging powers from which it seeks inward investment and market access.

Second, the deterioration in US–China relations means the UK may come under increasing pressure from the United States to take a tough line with China. The controversy over Huawei’s role in delivering 5G networks may become a more regular feature of transatlantic debates, with Britain facing Chinese economic pressure on one side and a squeeze from America over security issues on the other, without the weight of the EU behind it.  

A new prime minister should consider whether the UK’s interests are served by a security role in east Asia, and whether it has the capability to play one.

The UK remains a party to the Five Power Defence Arrangements. The Royal Navy has conducted freedom of navigation exercises in the South China Sea, prompting a rebuke from Beijing. It has also taken steps to deepen security ties with Japan.

But the UK government has struggled to present a coherent position. Some cabinet ministers have sought to open doors to the Chinese market at the same time as others announced their intentions to send aircraft carriers to the Pacific. The next PM will need to find a balance between China and the US, or accept the consequences of more directly taking sides on disputes about trade, technology, and security.

4. How can the contradictions between UK foreign and domestic policy be reconciled?

One of the many problems with the vague and unhelpful slogan ‘Global Britain’ is how it jars with many aspects of domestic policy. This incoherence reduces Britain’s foreign policy credibility and effectiveness.

Britain has actively supported the UN-led Yemen peace process while continuing to support Saudi Arabia’s military campaign through arms sales. Britain wants to build a new ambitious independent trade policy while restricting the migration that is crucial for services trade. British foreign secretaries trumpet the UK’s soft power while the Home Office deports members of the Windrush generation, bungles EU citizenship applications and sets unreasonable burdens for many people seeking visas simply to visit the country.

Global universities are celebrated while international students had their post-study visas cut (a policy that sensibly is likely to be reversed). Britain advocates international tax compliance and transparency while not taking robust steps to regulate the tax haven role played by crown dependencies and overseas territories.

A new prime minister has the chance to get to grips with these inconsistencies and develop foreign and domestic policies which are more coherent and self-re-enforcing.

5. At what level should Britain’s international ambitions be funded?

Successive governments have celebrated the fact the UK is the only Western country to spend 2% of GDP on defence and 0.7% on development. However, this masks some real pressures in the system.

There are significant problems in the defence budget and a growing gap between commitments and committed funds. Meanwhile, the funding of Britain’s diplomacy has been cut by successive governments – Labour, Conservative and coalition – for much of the last 20 years. Numerous bodies have highlighted the problems facing the overstretched and underfunded Foreign Office. Where would defence and diplomacy sit in the new prime minister’s hierarchy of priorities?

The problem is not purely one of funding, but the gap between ambitions, rhetoric and resources. It is not sustainable for British ministers to trumpet Britain’s global ambitions while not properly funding the tools of its influence abroad.

It would be reasonable and understandable for a new prime minister to adjust that ambition and tone down the rhetoric, or alternatively to address resource pressures by investing in diplomacy and defence. But that choice should be informed by a sober reflection on Britain’s international position and interests as it leaves the EU. Brexit offers a chance to revisit assumptions that have guided British policy for a generation. A new prime minister should seize this opportunity.

A realistic vision for the future

All these issues will be more pronounced if the UK leaves the EU with no deal at the end of October. ‘No deal’ would be not simply an economic shock but a diplomatic rupture that will colour the UK’s capacity to negotiate a new relationship with the EU, which will be the first order of business after a ‘no deal’ exit. Trust will be in short supply.

Even if they don’t get to vote on the new prime minister, the public deserves serious answers to these and other questions from the men who want to lead the country. Not the platitudes of ‘Global Britain’ or a reflexive and unexamined British exceptionalism, but a serious, realistic assessment of how Britain will cope with the disruptions of leaving the EU and how it might thrive outside the regional bloc it has been a part of for more than 45 years.




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Brexit, Party Politics and the Next Prime Minister

Invitation Only Research Event

15 July 2019 - 8:30am to 9:30am

Chatham House | 10 St James's Square | London | SW1Y 4LE

Event participants

Daniel Finkelstein OBE, Associate Editor, The Times; Conservative Member of the House of Lords; Chairman, Onward 
Chair: Thomas Raines, Head, Europe Programme, Chatham House

With the new leader of the Conservative party due to be announced on 23 July, what are the prospects for the party and the country?

On Brexit, the new prime minister faces most of the same challenges and constraints as Theresa May. The leadership contenders have outlined their ambitions for a revised deal, but with the EU insisting negotiations are over, their room for manoeuvre appears to be limited. Furthermore, even with a new leader at the helm, important divisions remain among voters about what shape Brexit and the future UK-EU relationship should take. If the EU won’t change the deal, and parliament won’t accept it, how can the deadlock be broken? Is a 'No Deal' Brexit politically deliverable? Or could there be a general election later in 2019? Can the Conservative party survive a pre-Brexit election intact?

Beyond Brexit, what are the other choices, in both domestic and foreign policy, facing the next prime minister? How might the decisions he makes affect the future of the party and British politics more broadly?

In this session, the speaker will share his reflections on the likely result of the leadership election, and what lies beyond it.

Attendance at this event is by invitation only.

Event attributes

Chatham House Rule

Alina Lyadova

Europe Programme Coordinator




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In Next Round of EU Negotiations, Britain Faces Familiar Pitfalls

31 January 2020

Thomas Raines

Director, Europe Programme

Professor Richard G Whitman

Associate Fellow, Europe Programme
Despite being free of the constraints and the theatre of a hung parliament, there is a risk that over the coming year the British government repeats too many of the mistakes of the withdrawal negotiations.

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The Elizabeth Tower remains under renovation on 31 January 2020. Photo: Getty Images.

Whether feared or longed for, Brexit day has arrived. It is positive for all sides that the process is thus far managed and ordered, with debts paid, rights guaranteed and borders still invisible on the island of Ireland. But in a difficult new phase of negotiations, as the UK and EU try to hammer out the terms of their relationship after 2020, Britain is at risk of repeating many of its mistakes from the withdrawal talks.

First, the government, through the negotiation timeline, has reduced its own room for manoeuvre. The failure of the initial withdrawal agreement and subsequent turbulent politics have reduced a planned 21-month transition to an 11-month one. Even though half the original negotiation time has been lost, 31 December 2020 remains in place and indeed has been written into UK law as the date the transition arrangement ends. Boris Johnson has followed Theresa May in investing symbolism and significance in an arbitrary date.

By promising not to extend negotiations, the UK is boxing itself in, creating domestic political barriers where it may well need flexibility. The familiar face of Michel Barnier, who proved adept in leading the withdrawal negotiations for the EU side, will be back in phase two to tell Britain the clock is ticking. This new timeline is intended to focus minds but more likely it will limit ambitions. 

Second, this government has continued the pattern of its predecessor in making no effort to manage public expectations about the consequences of Brexit. It is naïve to have followed the last years of British politics and expect an outbreak of sobriety and levelheadedness. The entrenched positions of each side have offered little political space or electoral incentive for realism.

During the 2020 transition period, the UK will lose the political rights of EU membership but it will retain the benefits and obligations. Most citizens and business will not be able to tell the difference. But a reckoning is inevitable. There will come a moment when the effects of this slow-motion political revolution – particularly in the hard form envisioned by Boris Johnson – become real, when the trade-offs and compromises, especially for business and the economy, will bite. The public deserve some realism about the price of sovereignty.

Third, there is a risk that government remains underprepared. While its headline goals are clear – at least in terms of what it does not want – the UK government will need thorough, realistic and coherent proposals on what it wants in every area of negotiations, and crucially develop a process by which to make political trade-offs between the demands of different sectors and issues. The government must also then prepare for their implementation in every area. This would be a huge challenge even if the final destination was already known, which it is not. 

Fourth, the continued uncertainty in the process means businesses and civil servants will again be left with little time to adapt to what will face them in January 2021 and must prepare for multiple outcomes.

‘Transition’ has always been a misleading term, since it implies clarity about the destination to which the UK–EU relationship will be transitioning. The government’s red lines for that future relationship provide a sketch: outside of the single market and the jurisdiction of the European Court of Justice, with an independent trade policy and free movement ended.

But businesses and civil servants are not likely to know until very late in the process if the basis for future trade with the EU will be in the form of a free trade agreement, to be negotiated and implemented by the end of the year, or no trade deal at all. This last outcome is a realistic prospect.

Michel Barnier speaks in the European Parliament on 29 January. Photo: Getty Images.

During withdrawal negotiations, the extensions were both unlimited in number and required decisions only at the last moment. In this phase, the talks may only be extended once, and that decision must be taken six months from the final deadline. It is difficult to see circumstances in which Boris Johnson agrees to break a political promise and manifesto pledge when he still has six more months to achieve his desired outcome.

The UK, it is often noted, is already fully compliant with EU law and this shared starting point is often cited as a reason this negotiation will be simple, since the parties begin in alignment. But this novel negotiation will create new trade barriers in goods and services rather than remove them. Trade deals are often politically difficult since they create winners and losers. The Brexit negotiations, in terms of UK–EU trade at least, will generally create only different levels of losers, on both sides of the Channel.

That means difficult politics, challenging negotiations and hard compromises, another reason to expect some ugly politics along the way and accept that failure is a plausible outcome.

We do not yet know how Brexit will change Britain in the long term, whether a settled majority will ever come to view it as political folly or liberation, choice or inevitability. If its politically fragile union can withstand the pressures of the next few years, the UK may yet find a new stable position on the EU’s periphery and, after a period of economic adjustment, begin to address the many pressing domestic challenges which have suffered from neglect amid the all-consuming Brexit saga.

But whatever happens in this next chapter, the EU can no longer be an excuse for national problems. As the UK takes back control it also returns accountability. In the future, there will be no one else to credit or to blame.




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A Credit-fuelled Economic Recovery Stores Up Trouble for Turkey

17 February 2020

Fadi Hakura

Consulting Fellow, Europe Programme
Turkey is repeating the mistakes that led to the 2018 lira crisis and another freefall for the currency may not be far off.

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Headquarters of the Central Bank of the Republic of Turkey. Photo: Getty Images.

Since the 2018 economic crisis, when the value of the lira plummeted and borrowing costs soared, Turkey’s economy has achieved a miraculous ‘V-shaped’ economic recovery from a recession lasting three quarters to a return back to quarterly growth above 1 per cent in the first three months of 2019.

But this quick turnaround has been built on vast amounts of cheap credit used to re-stimulate a consumption and construction boom. This so-called ‘triple C’ economy generated a rapid growth spurt akin to a modestly able professional sprinter injected with steroids.

This has made the currency vulnerable. The lira has steadily depreciated by 11 per cent against the US dollar since the beginning of 2019 and crossed the rate of 6 lira versus the US dollar on 7 February. And there are further warning signs on the horizon.

Credit bonanza

Statistics reveal that Turkish domestic credit grew by around 13 per cent on average throughout 2019.  The credit bonanza is still ongoing. Mortgage-backed home sales jumped by a record high of 600 per cent last December alone and the 2019 budget deficit catapulted by 70 per cent due to higher government spending.

Turkey’s central bank fuelled this credit expansion by cutting interest rates aggressively to below inflation and, since the start of this year, purchasing lira-denominated bonds equivalent to around one-third of total acquisitions last year to push yields lower.

Equally, it has linked bank lending to reserve requirements – the money that banks have to keep at the central bank – to boost borrowings via state and private banks. Banks with a ‘real’ loan growth (including inflation) of between 5 and 15 per cent enjoy a 2 per cent reserve ratio on most lira deposits, which authorities adjusted from an earlier band of 10-20 per cent that did not consider double-digit inflation.

Cumulatively, bond purchases (effectively quantitative easing) and reserve management policies have also contributed to eased credit conditions.

Commercial banks have also reduced deposit rates on lira accounts to less than inflation to encourage consumption over saving. Together with low lending rates, the boost to the economy has flowed via mortgages, credit card loans, vehicle leasing transactions and general business borrowings.

Accordingly, stimulus is at the forefront of the government’s economic approach, as it was in 2017 and 2018. It does not seem to be implementing structural change to re-orient growth away from consumption towards productivity. 

In addition, governance is, again, a central issue. President Recep Tayyip Erdogan’s near total monopolization of policymaking means he guides all domestic and external policies. He forced out the previous central bank governor, Murat Cetinkaya, in July 2019 because he did not share the president’s desire for an accelerated pace of interest rate reductions.

New challenges

Despite the similarities, the expected future financial turbulence will be materially different from its 2018 predecessor in four crucial respects. 

Firstly, foreign investors will only be marginally involved. Turkey has shut out foreign investors since 2018 from lira-denominated assets by restricting lira swap arrangements. Unsurprisingly, the non-resident holdings of lira bonds has plummeted from 20 per cent in 2018 to less than 10 per cent today.

Secondly, the Turkish government has recently introduced indirect domestic capital controls by constraining most commercial transactions to the lira rather than to the US dollar or euro to reduce foreign currency demand in light of short-term external debt obligations of $191 billion.

Thirdly, the Turkish state banks are intervening quite regularly to soften Lira volatility, thereby transitioning from a ‘free float’ to a ‘managed float’. So far, they have spent over $37 billion over the last two years in a futile effort to buttress the lira. This level of involvement in currency markets cannot be maintained.

Fourthly, the Turkish state is being far more interventionist in the Turkish stock exchange and bond markets to keep asset prices elevated. Government-controlled local funds have participated in the Borsa Istanbul and state banks in sovereign debt to sustain rallies or reverse a bear market.  

All these measures have one running idea: exclude foreign investors and no crisis will recur. Yet, when the credit boom heads to a downturn sooner or later, Turks will probably escalate lira conversions to US dollars; 51 per cent of all Turkish bank deposits are already dollar-denominated and the figure is still rising.

If Turkey’s limited foreign reserves cannot satisfy the domestic dollar demand, the government may have to impose comprehensive capital controls and allow for a double digit depreciation in the value of the lira to from its current level, with significant repercussions on Turkey’s political stability and economic climate.

To avoid this scenario, it needs to restore fiscal and monetary prudence, deal the with the foreign debt overhang in the private sector and focus on productivity-improving economic and institutional reforms to gain the confidence of global financial markets and Turks alike.




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Biochemical and structural insights into how amino acids regulate pyruvate kinase muscle isoform 2 [Enzymology]

Pyruvate kinase muscle isoform 2 (PKM2) is a key glycolytic enzyme involved in ATP generation and critical for cancer metabolism. PKM2 is expressed in many human cancers and is regulated by complex mechanisms that promote tumor growth and proliferation. Therefore, it is considered an attractive therapeutic target for modulating tumor metabolism. Various stimuli allosterically regulate PKM2 by cycling it between highly active and less active states. Several small molecules activate PKM2 by binding to its intersubunit interface. Serine and cysteine serve as an activator and inhibitor of PKM2, respectively, by binding to its amino acid (AA)-binding pocket, which therefore represents a potential druggable site. Despite binding similarly to PKM2, how cysteine and serine differentially regulate this enzyme remains elusive. Using kinetic analyses, fluorescence binding, X-ray crystallography, and gel filtration experiments with asparagine, aspartate, and valine as PKM2 ligands, we examined whether the differences in the side-chain polarity of these AAs trigger distinct allosteric responses in PKM2. We found that Asn (polar) and Asp (charged) activate PKM2 and that Val (hydrophobic) inhibits it. The results also indicate that both Asn and Asp can restore the activity of Val-inhibited PKM2. AA-bound crystal structures of PKM2 displayed distinctive interactions within the binding pocket, causing unique allosteric effects in the enzyme. These structure-function analyses of AA-mediated PKM2 regulation shed light on the chemical requirements in the development of mechanism-based small-molecule modulators targeting the AA-binding pocket of PKM2 and provide broader insights into the regulatory mechanisms of complex allosteric enzymes.




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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.




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Structure of an ancestral mammalian family 1B1 cytochrome P450 with increased thermostability [Enzymology]

Mammalian cytochrome P450 enzymes often metabolize many pharmaceuticals and other xenobiotics, a feature that is valuable in a biotechnology setting. However, extant P450 enzymes are typically relatively unstable, with T50 values of ∼30–40 °C. Reconstructed ancestral cytochrome P450 enzymes tend to have variable substrate selectivity compared with related extant forms, but they also have higher thermostability and therefore may be excellent tools for commercial biosynthesis of important intermediates, final drug molecules, or drug metabolites. The mammalian ancestor of the cytochrome P450 1B subfamily was herein characterized structurally and functionally, revealing differences from the extant human CYP1B1 in ligand binding, metabolism, and potential molecular contributors to its thermostability. Whereas extant human CYP1B1 has one molecule of α-naphthoflavone in a closed active site, we observed that subtle amino acid substitutions outside the active site in the ancestor CYP1B enzyme yielded an open active site with four ligand copies. A structure of the ancestor with 17β-estradiol revealed only one molecule in the active site, which still had the same open conformation. Detailed comparisons between the extant and ancestor forms revealed increases in electrostatic and aromatic interactions between distinct secondary structure elements in the ancestral forms that may contribute to their thermostability. To the best of our knowledge, this represents the first structural evaluation of a reconstructed ancestral cytochrome P450, revealing key features that appear to contribute to its thermostability.




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Specificity and affinity of the N-terminal residues in staphylocoagulase in binding to prothrombin [Computational Biology]

In Staphylococcus aureus–caused endocarditis, the pathogen secretes staphylocoagulase (SC), thereby activating human prothrombin (ProT) and evading immune clearance. A previous structural comparison of the SC(1–325) fragment bound to thrombin and its inactive precursor prethrombin 2 has indicated that SC activates ProT by inserting its N-terminal dipeptide Ile1-Val2 into the ProT Ile16 pocket, forming a salt bridge with ProT's Asp194, thereby stabilizing the active conformation. We hypothesized that these N-terminal SC residues modulate ProT binding and activation. Here, we generated labeled SC(1–246) as a probe for competitively defining the affinities of N-terminal SC(1–246) variants preselected by modeling. Using ProT(R155Q,R271Q,R284Q) (ProTQQQ), a variant refractory to prothrombinase- or thrombin-mediated cleavage, we observed variant affinities between ∼1 and 650 nm and activation potencies ranging from 1.8-fold that of WT SC(1–246) to complete loss of function. Substrate binding to ProTQQQ caused allosteric tightening of the affinity of most SC(1–246) variants, consistent with zymogen activation through occupation of the specificity pocket. Conservative changes at positions 1 and 2 were well-tolerated, with Val1-Val2, Ile1-Ala2, and Leu1-Val2 variants exhibiting ProTQQQ affinity and activation potency comparable with WT SC(1–246). Weaker binding variants typically had reduced activation rates, although at near-saturating ProTQQQ levels, several variants exhibited limiting rates similar to or higher than that of WT SC(1–246). The Ile16 pocket in ProTQQQ appears to favor nonpolar, nonaromatic residues at SC positions 1 and 2. Our results suggest that SC variants other than WT Ile1-Val2-Thr3 might emerge with similar ProT-activating efficiency.




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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.




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NAD+ biosynthesis in bacteria is controlled by global carbon/nitrogen levels via PII signaling [Microbiology]

NAD+ is a central metabolite participating in core metabolic redox reactions. The prokaryotic NAD synthetase enzyme NadE catalyzes the last step of NAD+ biosynthesis, converting nicotinic acid adenine dinucleotide (NaAD) to NAD+. Some members of the NadE family use l-glutamine as a nitrogen donor and are named NadEGln. Previous gene neighborhood analysis has indicated that the bacterial nadE gene is frequently clustered with the gene encoding the regulatory signal transduction protein PII, suggesting a functional relationship between these proteins in response to the nutritional status and the carbon/nitrogen ratio of the bacterial cell. Here, using affinity chromatography, bioinformatics analyses, NAD synthetase activity, and biolayer interferometry assays, we show that PII and NadEGln physically interact in vitro, that this complex relieves NadEGln negative feedback inhibition by NAD+. This mechanism is conserved in distantly related bacteria. Of note, the PII protein allosteric effector and cellular nitrogen level indicator 2-oxoglutarate (2-OG) inhibited the formation of the PII-NadEGln complex within a physiological range. These results indicate an interplay between the levels of ATP, ADP, 2-OG, PII-sensed glutamine, and NAD+, representing a metabolic hub that may balance the levels of core nitrogen and carbon metabolites. Our findings support the notion that PII proteins act as a dissociable regulatory subunit of NadEGln, thereby enabling the control of NAD+ biosynthesis according to the nutritional status of the bacterial cell.




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Spectral and photochemical diversity of tandem cysteine cyanobacterial phytochromes [Plant Biology]

The atypical trichromatic cyanobacterial phytochrome NpTP1 from Nostoc punctiforme ATCC 29133 is a linear tetrapyrrole (bilin)-binding photoreceptor protein that possesses tandem-cysteine residues responsible for shifting its light-sensing maximum to the violet spectral region. Using bioinformatics and phylogenetic analyses, here we established that tandem-cysteine cyanobacterial phytochromes (TCCPs) compose a well-supported monophyletic phytochrome lineage distinct from prototypical red/far-red cyanobacterial phytochromes. To investigate the light-sensing diversity of this family, we compared the spectroscopic properties of NpTP1 (here renamed NpTCCP) with those of three phylogenetically diverged TCCPs identified in the draft genomes of Tolypothrix sp. PCC7910, Scytonema sp. PCC10023, and Gloeocapsa sp. PCC7513. Recombinant photosensory core modules of ToTCCP, ScTCCP, and GlTCCP exhibited violet-blue–absorbing dark-states consistent with dual thioether-linked phycocyanobilin (PCB) chromophores. Photoexcitation generated singly-linked photoproduct mixtures with variable ratios of yellow-orange and red-absorbing species. The photoproduct ratio was strongly influenced by pH and by mutagenesis of TCCP- and phytochrome-specific signature residues. Our experiments support the conclusion that both photoproduct species possess protonated 15E bilin chromophores, but differ in the ionization state of the noncanonical “second” cysteine sulfhydryl group. We found that the ionization state of this and other residues influences subsequent conformational change and downstream signal transmission. We also show that tandem-cysteine phytochromes present in eukaryotes possess similar amino acid substitutions within their chromophore-binding pocket, which tune their spectral properties in an analogous fashion. Taken together, our findings provide a roadmap for tailoring the wavelength specificity of plant phytochromes to optimize plant performance in diverse natural and artificial light environments.




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A single amino acid substitution uncouples catalysis and allostery in an essential biosynthetic enzyme in Mycobacterium tuberculosis [Enzymology]

Allostery exploits the conformational dynamics of enzymes by triggering a shift in population ensembles toward functionally distinct conformational or dynamic states. Allostery extensively regulates the activities of key enzymes within biosynthetic pathways to meet metabolic demand for their end products. Here, we have examined a critical enzyme, 3-deoxy-d-arabino-heptulosonate 7-phosphate synthase (DAH7PS), at the gateway to aromatic amino acid biosynthesis in Mycobacterium tuberculosis, which shows extremely complex dynamic allostery: three distinct aromatic amino acids jointly communicate occupancy to the active site via subtle changes in dynamics, enabling exquisite fine-tuning of delivery of these essential metabolites. Furthermore, this allosteric mechanism is co-opted by pathway branchpoint enzyme chorismate mutase upon complex formation. In this study, using statistical coupling analysis, site-directed mutagenesis, isothermal calorimetry, small-angle X-ray scattering, and X-ray crystallography analyses, we have pinpointed a critical node within the complex dynamic communication network responsible for this sophisticated allosteric machinery. Through a facile Gly to Pro substitution, we have altered backbone dynamics, completely severing the allosteric signal yet remarkably, generating a nonallosteric enzyme that retains full catalytic activity. We also identified a second residue of prime importance to the inter-enzyme communication with chorismate mutase. Our results reveal that highly complex dynamic allostery is surprisingly vulnerable and provide further insights into the intimate link between catalysis and allostery.




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The Belt and Road Initiative: geo-economics and Indo-Pacific security competition

8 January 2020 , Volume 96, Number 1

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.




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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.




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Wartime paradigms and the future of western military power

4 March 2020 , Volume 96, Number 2

Olivier Schmitt

From the perception of the imminence of threats at the political level to the seizing of initiative through proper timing at the tactical level, temporality is directly related to war and warfare. Yet, despite some analyses of the importance of time at the political/grand strategic level (usually by scholars) and at the tactical level (usually by military professionals) there is surprisingly little discussion of the impact of time on the preparation and the conduct of warfare. This article introduces the concept of ‘wartime paradigm’ as a heuristic device to understand the relationship between the perception of time and the conduct of warfare, and argues that after the Cold War, a specific ‘wartime paradigm’ combining an optimization for speed and an understanding of war as risk management has guided western warfare, from force structure to the conduct of actual operations. It shows how the changing character of warfare directly challenges this wartime paradigm and why, if western forces want to prevail in future conflicts, the establishment of a new wartime paradigm guiding technological improvements and operational concepts is critical.




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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.




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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.




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Webinar: Implications of the COVID-19 Pandemic for African Economies and Development

Research Event

21 April 2020 - 4:30pm to 5:30pm

Event participants

Dr Hafez Ghanem, Vice President for Africa, World Bank
Chair: Elizabeth Donnelly, Deputy Director, Africa Programme, Chatham House

Dr Hafez Ghanem discusses the implications of the COVID-19 pandemic for African economies and their development and poverty reduction efforts, and assesses the priorities and obstacles for establishing a comprehensive response to the crisis.
 
While the acute strain placed on health systems by the COVID-19 pandemic is already in evidence, the long-term economic fallout from the crisis is yet to fully manifest.
 
For Africa it is the economic impact that may leave the most enduring legacy: from the direct expense of measures to treat, detect and reduce the spread of the virus; to the indirect costs of domestic lockdown measures, global supply chain disruptions and plummeting commodity prices.
 
As decision-makers globally start to plan for the scale of this economic shock, strategizing in and on Africa to meet the challenge will require unprecedented planning and commitment - and will need to be matched by support from international partners to enable long-term recovery.
 

Hanna Desta

Programme Assistant, Africa Programme




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Webinar: Implications of the COVID-19 Pandemic for Food Security and Resilience in Africa

Research Event

23 April 2020 - 1:00pm to 2:00pm

Event participants

Dr Arif Husain, Chief Economist and Director of Research, Assessment and Monitoring, United Nations World Food Programme
Respondent: Dr Leena Koni Hoffmann, Associate Fellow, Africa Programme, Chatham House
Chair: Professor Tim Benton, Research Director, Emerging Risks; Director, Energy, Environment and Resources Programme, Chatham House
Dr Arif Husain gives his assessment of the potential impact that the COVID-19 pandemic will have on food security in Africa and what can be done to prevent a food security emergency.
 
Linked to the immediate public health consequences of the COVID-19 pandemic are those of economic and food security, particularly significant for low- and middle-income countries. Currently more than 821 million people globally go hungry, with 100 million of those suffering acute hunger, and this will worsen if the evolving economic emergency becomes a food security emergency.
 
Sub-Saharan African countries rely on trade for food security and for revenue; they imported more than 40 million tons of cereal from around the world in 2018, according to the World Food Programme (WFP). The region faces stark new challenges due to the pandemic.

This event launches the WFP paper COVID-19: Potential impact on the world’s poorest people.

Department/project

Hanna Desta

Programme Assistant, Africa Programme




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Webinar: Weekly COVID-19 Pandemic Briefing

Members Event

22 April 2020 - 10:00am to 10:45am

Online

Event participants

Professor David Heymann CBE, Distinguished Fellow, Global Health Programme, Chatham House; Executive Director, Communicable Diseases Cluster, World Health Organization (1998-03)
Chair: Emma Ross, Senior Consulting Fellow, Global Health Programme, Chatham House

The fifth in a weekly series of interactive webinars on the coronavirus with Professor David Heymann helping us to understand the facts and make sense of the latest developments during the global crisis. 

The coronavirus pandemic continues expand and claim lives as it takes hold across the world. As countries grapple with how best to tackle the virus and the reverberations the pandemic is sending through their societies and economies, understanding of how the virus is behaving and what measures to combat it are working continues to advance. 

Professor Heymann is a world-leading authority on infectious disease outbreaks. He led the World Health Organization’s response to SARS and has been advising the organization on its response to the coronavirus. 

Members Events Team




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Webinar: Global Economic Recovery and Resilience to Systemic Shocks

Corporate Members Event Webinar

20 May 2020 - 5:00pm to 5:45pm
Add to Calendar

Francesca Viliani, Consultant Researcher, Global Health Programme, Chatham House; Director, Public Health, International SOS

Sven Smit, Co-Chair, McKinsey Global Institute and Senior Partner, McKinsey & Company, Amsterdam

Chair: Creon Butler, Research Director, Trade, Investment & New Governance Models: Director, Global Economy and Finance Programme, Chatham House

 

The outbreak of COVID-19 has demonstrated the wide-ranging and immediate impact a systemic shock can have on the global economy including the financial loss caused by the emergency shutdown of many retail operations, the loss of income for individuals who are forced to stay indoors and the major disruption to supply chains. The longer term impacts are still being realized and depend heavily on the ability of industry and the government to respond effectively to the direct economic shock caused by the pandemic.

Systemic shocks like the COVID-19 pandemic demand immediate responses, but should also encourage governments and industries to re-examine their recovery processes, their resilience and their forward planning. In this webinar, the panellists will discuss the short and long-term impacts of the current crisis and explore how industry can help ensure that the global economy is able to recover from, and build resilience to, future systemic shocks. How do business leaders move from making decisions to reimagining a ‘new normal’ and reforming their practices? What are the critical decisions that businesses should consider when planning for this 'new normal'? And how far can these decisions be based on expected changes to governmental or intergovernmental regulation of different sectors?   

This event is part of a fortnightly series of 'Business in Focus' webinars reflecting on the impact of COVID-19 on areas of particular professional interest for our corporate members and giving circles.

Not a corporate member? Find out more.




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Webinar: Weekly COVID-19 Pandemic Briefing – The Swedish Approach

Members Event Webinar

29 April 2020 - 10:00am to 11:00am

Online

Event participants

Professor Johan Giesecke, MD, PhD, Professor Emeritus of Infectious Disease Epidemiology, Karolinska Institute Medical University, Stockholm; State Epidemiologist, Sweden (1995-05)
Professor David Heymann CBE, Distinguished Fellow, Global Health Programme, Chatham House; Executive Director, Communicable Diseases Cluster, World Health Organization (1998-03)
Chair: Emma Ross, Senior Consulting Fellow, Global Health Programme, Chatham House

The coronavirus pandemic continues to claim lives around the world. As countries grapple with how best to tackle the virus, and the reverberations the pandemic is sending through their societies and economies, scientific understanding of how the COVID-19 virus is behaving and what measures might best combat it continues to advance.

Join us for the sixth in a weekly series of interactive webinars on the coronavirus with Professor David Heymann and special guest, Johan Giesecke, helping us to understand the facts and make sense of the latest developments in the global crisis. What strategy has Sweden embraced and why? Can a herd immunity strategy work in the fight against COVID-19? How insightful is it to compare different nations’ approaches and what does the degree of variation reveal?

Professor Heymann is a world-leading authority on infectious disease outbreaks. He led the World Health Organization’s response to SARS and has been advising the organization on its response to the coronavirus. 

Professor Giesecke is professor emeritus of Infectious Disease Epidemiology at the Karolinska Institute Medical University in Stockholm. He was state epidemiologist for Sweden from 1995 to 2005 and the first chief scientist of the European Centre for Disease Prevention and Control (ECDC) from 2005 to 2014.




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Webinar: European Democracy in the Last 100 Years: Economic Crises and Political Upheaval

Members Event Webinar

6 May 2020 - 1:00pm to 2:00pm

Event participants

Pepijn Bergsen, Research Fellow, Europe Programme, Chatham House

Dr Sheri Berman, Professor of Political Science, Barnard College

Chair: Hans Kundnani, Senior Research Fellow, Europe Programme, Chatham House

 

In the last 100 years, global economic crises from the Great Depression of the 1930s to the 2008 financial crash have contributed to significant political changes in Europe, often leading to a rise in popularity for extremist parties and politics. As Europe contends with a perceived crisis of democracy - now compounded by the varied responses to the coronavirus outbreak - how should we understand the relationship between externally-driven economic crises, political upheaval and democracy?

The panellists will consider the parallels between the political responses to some of the greatest economic crises Europe has experienced in the last century. Given that economic crises often transcend borders, why does political disruption vary between democracies? What can history tell us about the potential political impact of the unfolding COVID-19-related economic crisis? And will the unprecedented financial interventions by governments across Europe fundamentally change the expectations citizens have of the role government should play in their lives?

This event is based on a recent article in The World Today by Hans Kundnani and Pepijn Bergsen who are both researchers in Chatham House's Europe Programme. 'Crawling from the Wreckage' is the first in a series of articles that look at key themes in European political discourse from the last century. You can read the article here

This event is open to Chatham House Members. Not a member? Find out more.




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Reimagining Trade Rules to Address Climate Change in a Post-Pandemic World

Webinar Research Event

5 May 2020 - 2:00pm to 3:00pm

Event participants

James Bacchus, Distinguished University Professor of Global Affairs and Director of the Center for Global Economic and Environmental Opportunity at the University of Central Florida; Member and Chair, WTO Appellate Body, 1995 - 2003
Chair: Creon Butler, Director, Global Economy and Finance Programme, Chatham House

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

International trade has a crucial role to play in tackling climate change. The production and transport of goods is a major contributor to green-house gas emissions, as is the delivery of certain cross-border services. At the same time, it looks inevitable that the COVID-19 pandemic will lead to a radical re-think of global supply chains as companies and governments seek to build in greater resilience while at the same time preserving as far as possible the efficiency gains and lower costs that global supply chains generate when operating normally.

Future international trade rules will have a crucial role to play in addressing both challenges; they represent both an opportunity and a risk. If designed well, they could play a very important role in re-enforcing moves towards a more sustainable use of resources, greater overall alignment of economies with the Paris Agreement, and greater economic resilience. But they could also, if poorly designed and implemented, or overly influenced by strategic political considerations, have significant unintended and negative implications. These include: reduced economic efficiency, increased poverty, unnecessary economic decoupling and reduced consensus on the broader mitigation and adaptation measures required to meet the challenge of climate change.

Against this background, a number of key questions arise: In what areas, if any, do we need to modify or adapt key principles underlying the system of global trade rules in order to respond to the twin challenges of responding to climate change and building greater economic resilience?  Which are the most promising/practical areas on which trade policy experts should focus now to re-launch/re-energize discussions on WTO reform, including, for example, dispute settlement? What national economic policies will be needed to complement the development of new/reformed trade disciplines in these areas? How might future political changes, such as a change in the US administration, affect the prospects for and political momentum behind such deliberations? What in any eventuality is the best way to build the required political momentum?
 
This roundtable is convened by the Global Economy and Finance Programme and the US and the Americas Programme and it is part of the Chatham House Global Trade Policy Forum. The event 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.

Please note this event is taking place between 2pm to 3pm BST.




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Webinar: Weekly COVID-19 Pandemic Briefing – The Geopolitics of the Coronavirus

Members Event Webinar

6 May 2020 - 10:00am to 10:45am

Online

Event participants

Professor Ilona Kickbusch, Associate Fellow, Global Health Programme, Chatham House; Founding Director and Chair, Global Health Centre, Graduate Institute of International and Development Studies 
Professor David Heymann CBE, Distinguished Fellow, Global Health Programme, Chatham House; Executive Director, Communicable Diseases Cluster, World Health Organization (1998-03)
Chair: Emma Ross, Senior Consulting Fellow, Global Health Programme, Chatham House

The coronavirus pandemic continues to claim lives around the world. As countries grapple with how best to tackle the virus and the reverberations the pandemic is sending through their societies and economies, scientific understanding of how the coronavirus is behaving, and what measures might best combat it, continues to advance.

Join us for the seventh in a weekly series of interactive webinars on the coronavirus with Professor David Heymann and special guest Professor Ilona Kickbusch helping us to understand the facts and make sense of the latest developments in the global crisis.

What will the geopolitics of the pandemic mean for multilateralism? As the US retreats, what dynamics are emerging around other actors and what are the implications for the World Health Organization? Is the EU stepping up to play a bigger role in global health? Will the pandemic galvanize the global cooperation long called for?

Professor Heymann is a world-leading authority on infectious disease outbreaks. He led the World Health Organization’s response to SARS and has been advising the organization on its response to the coronavirus. 

Professor Kickbusch is one of the world’s leading experts in global health diplomacy and governance. She advises international organizations, national governments, NGOs and the private sector on new directions and innovations in global health, governance for health and health promotion.




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Webinar: Implications of the COVID-19 Pandemic for African Elections and Democracy

Research Event

6 May 2020 - 2:30pm to 3:30pm

Event participants

Dr Christopher Fomunyoh, Senior Associate and Regional Director for Central and West Africa, National Democratic Institute (NDI)
Chair: Elizabeth Donnelly, Deputy Director, Africa Programme, Chatham House
2020 was anticipated to be a year of landmark elections across Africa, including general elections scheduled in Somalia and Ethiopia – countries at critical junctures in their transitions to electoral democracy – as well as a re-run of annulled presidential elections in Malawi.
 
The COVID-19 pandemic has created new challenges for African countries seeking to hold elections or further democratization – including the practicalities of adapting containment measures to electoral processes in the context of strained financial and logistical resources. It may also be used as a pretext for the pursuit of repressive legislation and constitutional amendments to preclude elections or bolster authoritarianism, compounded by new constraints on accountability mechanisms such as election observation missions.
 
At this event, Dr Christopher Fomunyoh discusses the likely impact of the COVID-19 pandemic on elections and democracy in various African countries, as well as responses and measures to meet the multifaceted challenges posed.

Hanna Desta

Programme Assistant, Africa Programme




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Webinar: COVID-19 and the Impact on Latin American Migration

Research Event

14 May 2020 - 3:00pm to 4:00pm
Add to Calendar

Ambassador Arturo Sarukhan, Associate Fellow, US and the Americas Programme, Chatham House; Mexican Ambassador to the US, 2007 - 13
Professor Anita Isaacs, Benjamin R. Collins Professor of Social Sciences, Haverford College
Chair: Dr Christopher Sabatini, Senior Research Fellow for Latin America, US and the Americas Programme, Chatham House

The US government recently announced restrictions on immigration, stating the new measures were necessary due to COVID-19 and the effect the pandemic has had on the US economy. But what is the role of immigrants in the essential official and unofficial services in the COVID-19 stay-at-home era? How is COVID-19 affecting immigration from Central America and Mexico? 

Separately, there have also been instances of outbreaks among detainees in US Immigration and Customs Enforcement centers and claims that immigrants who are returning to Guatemala are spreading the virus. How have US immigration policies affected infection rates in Central America and Mexico and among its citizens?

Arturo Sarukhan, Mexican Ambassador to the US from 2007 - 13, and Anita Isaacs, Benjamin R. Collins Professor of Social Sciences, Haverford College, will join us to discuss the impact COVID-19 is having on migrants.

Chatham House would like to thank BTG Pactual, Cairn Energy plc, Diageo plc, Equinor, Fresnillo Management Services, HSBC Holdings plc and Wintershall Dea for their generous support of the Latin America Initiative.

This event is scheduled to take place from 15:00 – 16:00 BST.

US and Americas Programme




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Meeting the Promise of the 2010 Constitution: Devolution, Gender and Equality in Kenya

Research Event

12 May 2020 - 1:00pm to 2:00pm
Add to Calendar
Natasha Kimani, Academy Associate, Chatham House; Head of Partnerships and Programmes, Shujaaz Inc.
Chair: Tighisti Amare, Assistant Director, Africa Programme, Chatham House
While gender equality was enshrined in Kenyan law under the 2010 constitution, gender-based marginalization remains a significant issue across all levels of society. The advent of devolution in 2013 raised hopes of enhanced gender awareness in policymaking and budgeting, with the 47 newly instituted county governments expected to tackle the dynamics of inequality close to home, but implementation has so far failed to match this initial promise. As Kenya approaches the tenth anniversary of the constitution, and with the COVID-19 pandemic throwing the challenges of gender inequality into sharper relief, it is critical to ensure that constitutional pathways are followed with the requisite level of urgency, commitment and investment to address entrenched gender issues.
 
This event, which will launch the report, Meeting the Promise of the 2010 Constitution: Devolution, Gender and Equality in Kenya, will assess the current status of efforts to devolve and adopt gender-responsive budgeting and decision-making in Kenya, and the priorities and potential future avenues to tackle the implementation gap.
 
This event will be held on the record.

To express your interest in attending, please follow this link. You will receive a Zoom confirmation email should your registration be successful.

Hanna Desta

Programme Assistant, Africa Programme




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Webinar: Weekly COVID-19 Pandemic Briefing – Vaccines

Members Event Webinar

13 May 2020 - 10:00am to 10:45am
Add to Calendar

Chatham House | 10 St James's Square | London | SW1Y 4LE

Professor David Heymann CBE, Distinguished Fellow, Global Health Programme, Chatham House; Executive Director, Communicable Diseases Cluster, World Health Organization (1998-03)
Professor David Salisbury CB, Associate Fellow, Global Health Programme, Chatham House; Director of Immunization, Department of Health, London (2007-13)

Chair: Emma Ross, Senior Consulting Fellow, Global Health Programme, Chatham House

As countries grapple with how best to tackle the COVID-19 pandemic and the reverberations it is sending through their societies and economies, scientific understanding of how the virus is behaving, and what measures might best combat it, continues to advance. This briefing will focus on the progress towards and prospects for a coronavirus vaccine, exploring the scientific considerations, the production, distribution and allocation challenges as well as the access politics.

Join us for the eighth in a weekly series of interactive webinars on the coronavirus with Professor David Heymann and special guest, Professor David Salisbury, helping us to understand the facts and make sense of the latest developments in the global crisis. With 80 candidate vaccines reported to be in development, how will scientists and governments select the 'right' one? What should be the role of global leadership and international coordination in the development and distribution of a new vaccine? And can equitable access be ensured across the globe?

Professor Heymann is a world-leading authority on infectious disease outbreaks. He led the World Health Organization’s response to SARS and has been advising the organization on its response to the coronavirus.

Professor Salisbury was director of immunization at the UK Department of Health from 2007 to 2013. He was responsible for the national immunization programme and led the introduction of many new vaccines. He previously chaired the WHO’s Strategic Advisory Group of Experts on Immunization and served as co-chair of the Pandemic Influenza group of the G7 Global Health Security Initiative.

This event will be livestreamed.




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Webinar: International Humanitarian Law Amid Coronavirus

Members Event Webinar

15 May 2020 - 1:00pm to 2:00pm
Add to Calendar

Emanuela-Chiara Gillard, Associate Fellow, International Law Programme, Chatham House

Chair: Chanu Peiris, Programme Manager, International Law Programme, Chatham House

Further speakers to be announced.

In April 2020, UN Secretary General Antonio Guterres called for a global ceasefire in order for communities and states to focus efforts on responding to the coronavirus outbreak. The consequences of armed conflict – including displacement, detention, lack of access to health services and disrupted social infrastructures – mean that those in conflict-ridden areas are amongst the most vulnerable to the virus. Observing international humanitarian law (IHL) could be one way of safeguarding against, at least, the provision of vital medical supplies and personnel for vulnerable groups. Against the backdrop of a growing health and economic emergency that is otherwise dominating government agendas, how do we emphasise the importance of humanitarian action and guarantee - or improve - compliance?

The panellists will discuss the remit and limitations of international humanitarian law and how the pandemic might complicate compliance. What is the framework for humanitarian action under international humanitarian law? What are the challenges to delivering relief? And how has COVID-19 impacted humanitarian action in conflict-ridden areas?

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




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Year Two of the Abe Administration: Prospects for the Future of Japanese Foreign Policy and UK-Japan Relations

Research Event

11 February 2014 - 3:00pm to 5:00pm

Chatham House, London

Event participants

Kiichi Fujiwara, Professor of International Politics, Graduate School for Law and Politics, Tokyo University
Yuichi Hosoya, Professor of International Politics, Faculty of Law, Keio University
Akiko Yamanaka, Senior Visiting Research Fellow, Churchill College, University of Cambridge; Vice Minister for Foreign Affairs of Japan (2005-2006)
Chair: John Swenson-Wright, Senior Consulting Fellow, Asia Programme, Chatham House 

As Prime Minster Abe enters his second year in office, the speakers will consider future prospects for Japanese foreign policy and UK-Japan relations. 

This event is funded by the Nippon Foundation. It is held in partnership with the Nippon Foundation and the Great Britain Sasakawa Foundation.

THIS EVENT IS NOW FULL AND REGISTRATION HAS CLOSED.

Department/project




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Islamism and Its Alternatives in the GCC

Research Event

14 December 2014 - 9:00am to 15 December 2014 - 2:00pm

Doha, Qatar

This expert-level workshop will bring together around 30 Gulf scholars, experts and practitioners from a variety of professional and academic backgrounds to share their analysis and research on the role of Islam in social and political movements in the GCC countries, as well as alternatives to Islamism. It will place political Islam in historical context, explore the differences between different strands of political Islam and the ways in which different country contexts have shaped the behaviour of movements that claim to have religious legitimacy, such as the institutions and legal regulations governing political movements.

This event is part of Chatham House’s Future Trends in the GCC research project, and is held in partnership with Qatar University’s Gulf Studies Center in Doha, Qatar.

Event attributes

External event




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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.




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Inside Syria: Life Amidst Revolution and War

Members Event

28 January 2016 - 1:00pm to 2:00pm

Chatham House, London

Event participants

Mina Al-Oraibi, Journalist on Middle East affairs
Robin Yassin-Kassab, Author, Burning Country: Syrians in Revolution and War
Chair: Dr Neil Quilliam, Acting Head, Middle East and North Africa Programme, Chatham House

In 2011, many Syrians took to the streets of Damascus to demand the overthrow of the government of Bashar al-Assad. Today, much of Syria has become a warzone and many worry that the country is on the brink of collapse.

Drawing on first-hand testimonies from opposition fighters, exiles and human rights activists, the panel will explore the complicated reality of life in present-day Syria. Looking at the militarization of the uprising, the rise of the Islamists and sectarian warfare, and the role of Syria’s government in the conflict, the speakers will discuss the issues from the grassroots to the geopolitical, including the role of the international community in bringing to an end the bloodshed.

This event is now full and registration has closed. An audio recording will be made available shortly after the event has taken place.

Members Events Team




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Why Turkey’s Disapproval of the West’s Response to the Coup Has Limited Merit

10 August 2016

Fadi Hakura

Consulting Fellow, Europe Programme
Although Turks across the political and ideological spectrum are seething at the West’s apparently lukewarm condemnation of the abortive coup on 15 July, there are valid reasons behind the response.

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A Turkish flag attached to helium balloons as people gather to protest at Konak Square, Izmir during the July 15 failed military coup attempt. Photo by Getty Images

Signs of growing anger at the restrained denunciation of Pennsylvania-based Muslim cleric Fethullah Gulen - whose followers are thought to have played a key role in the attempted coup - are being vocalised more and more, but this criticism only shows part of the true picture.

It is true that prominent liberal Turkish intellectual Soli Ozel spoke for many when he criticised EU politicians and Western media for failing to recognise the “invaluable democratic resistance shown by all political parties in a parliament bombed by war planes”, as well as demonstrating “a lack of sensitivity, empathy and solidarity that cannot be easily digested” by not sending anyone from an EU institution to offer solidarity with the Turkish parliament.

The criticism is reasonable - officials from Western governments and regional institutions such as the Council of Europe exhibited unconditional solidarity with Ukraine during its bitter feud with Russia, which leads some to believe that Muslim-majority Turkey does not apparently deserve the same treatment as its neighbours also experiencing an unlawful attempt to seize control of the state.

Moral authority at risk

It is also right that the West should have censured the coup plotters more forcefully and built upon Turkey’s fragile unity to encourage the country to pursue further democratic reform. To quote former Swedish Prime Minister and Foreign Minister Carl Bildt: “Europe risks losing its moral authority if it does not appear particularly engaged in dealing with the coup itself.”

In addition, the EU’s strong criticism of Turkey but not France, for imposing a state of emergency and for temporarily suspending the European Convention on Human Rights, undeniably, smacks of double-standards.

However, some of the criticism falls short. To begin with, the West’s tepidity can be explained (though not wholly justified) by Erdogan’s abrasive behaviour at home and towards Western and international media.

Just three days after the coup, Erdogan threatened in his characteristically defiant tone to revive the controversial construction plans that sparked the 2013 Gezi Park protests, saying: “If we want to preserve our history, we must rebuild this historic [Ottoman-era barracks] structure, [and] we will rebuild it.”

It is also fair for Turkey to be reproached for the widespread crackdown against tens of thousands of suspected Gulenists in the aftermath of the coup. Even if it is conceivable that all 1,577 university deans who were forced to resign were Gulenists, this action will also have a lasting negative impact on the reputations and career prospects of academics unconnected to Gulen.

Fervour against Gulenism

The vigilance by the West is understandable given the Turkish government’s fervour against Gulenism in the immediate post-coup period. It would make no sense for the West to attack the coup and yet, at the same time, equivocate on flagrant violations of due process and human rights. Both efforts are mutually inclusive and identifying such violations has the greatest potential to encourage policy reversals or corrective measures.

Similarly understandable is the attention on Erdogan himself. He is the most formidable and powerful figure in a hierarchical and top-down political system, able to make fateful decisions with few effective checks and balances. He single-handedly replaced Ahmet Davutoglu as prime minister with Binali Yildirim in a clear breach of the Turkish constitution.

Despite Erdogan’s tactical attempts at embracing all the opposition parties apart from the pro-Kurdish Peoples’ Democratic Party (HDP), his refusal to renounce his ambition to transform Turkey into a powerful executive presidency indicates that this fragile political unity will not last.

Only the West has the wherewithal to moderate his policies by continuing to express its friendship with Turkey, whilst not shying away from closely monitoring, scrutinising and commenting on the post-coup developments.

Contact Chatham House Feedback

Join the conversation about this piece on Facebook




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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.

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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




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Pace Your Prose — Three Thoughts on Timing

Have you ever come across a section of a book where it felt like everything happened at breakneck speed, and you could only just barely read fast enough to keep up? Or have you seen the opposite, where it’s all nice and slow and mellow, and where you’re able to really take your time and enjoy the beauty of the words?

That’s the kind of thing I’ll be musing on today. Prose and pacing. Time and reading.

Do note, this is not about how to pace your story, that’s an entirely different topic.

The Basics

Most writers will at one point or another have heard that a full stop is a signal for the reader to breathe. The shorter the sentences are, the quicker the breathing becomes, like when you’re excited. With longer sentences, the breaths grow longer, and deeper, and you calm down.

And when you write really long sentences and don’t include any commas or other forms of punctuation your reader might just run out of breath and begin to feel a little panicked.

There’s no ideal sentence length to strive for – rather the opposite.

Continue reading Pace Your Prose — Three Thoughts on Timing at Mythic Scribes.



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