Qiang Tian
Oct 1, 2004; 3:960-969
Research

William M. Old
Oct 1, 2005; 4:1487-1502
Research

Leigh Anderson
Apr 1, 2006; 5:573-588
Research

Mathias Uhlén
Dec 1, 2005; 4:1920-1932
Research

Claudio P. Albuquerque
Jul 1, 2008; 7:1389-1396
Research

Ignat V. Shilov
Sep 1, 2007; 6:1638-1655
Technology

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

Yasushi Ishihama
Sep 1, 2005; 4:1265-1272
Research

Linn Fagerberg
Feb 1, 2014; 13:397-406
Research

Jesper V. Olsen
Dec 1, 2005; 4:2010-2021
Technology

Jürgen Cox
Sep 1, 2014; 13:2513-2526
Technological Innovation and Resources

Despite its major importance in human health, the metabolic potential of the human gut microbiota is still poorly understood. We have recently shown that biosynthesis of Ruminococcin C (RumC), a novel ribosomally synthesized and posttranslationally modified peptide (RiPP) produced by the commensal bacterium Ruminococcus gnavus, requires two radical SAM enzymes (RumMC1 and RumMC2) catalyzing the formation of four Cα-thioether bridges. These bridges, which are essential for RumC's antibiotic properties against human pathogens such as Clostridium perfringens, define two hairpin domains giving this sactipeptide (sulfur-to-α-carbon thioether–containing peptide) an unusual architecture among natural products. We report here the biochemical and spectroscopic characterizations of RumMC2. EPR spectroscopy and mutagenesis data support that RumMC2 is a member of the large family of SPASM domain radical SAM enzymes characterized by the presence of three [4Fe-4S] clusters. We also demonstrate that this enzyme initiates its reaction by Cα H-atom abstraction and is able to catalyze the formation of nonnatural thioether bonds in engineered peptide substrates. Unexpectedly, our data support the formation of a ketoimine rather than an α,β-dehydro-amino acid intermediate during Cα-thioether bridge LC–MS/MS fragmentation. Finally, we explored the roles of the leader peptide and of the RiPP precursor peptide recognition element, present in myriad RiPP-modifying enzymes. Collectively, our data support a more complex role for the peptide recognition element and the core peptide for the installation of posttranslational modifications in RiPPs than previously anticipated and suggest a possible reaction intermediate for thioether bond formation.

Leukocidin ED (LukED) is a pore-forming toxin produced by Staphylococcus aureus, which lyses host cells and promotes virulence of the bacteria. LukED enables S. aureus to acquire iron by lysing erythrocytes, which depends on targeting the host receptor Duffy antigen receptor for chemokines (DARC). The toxin also targets DARC on the endothelium, contributing to the lethality observed during bloodstream infection in mice. LukED is comprised of two monomers: LukE and LukD. LukE binds to DARC and facilitates hemolysis, but the closely related Panton–Valentine leukocidin S (LukS-PV) does not bind to DARC and is not hemolytic. The interaction of LukE with DARC and the role this plays in hemolysis are incompletely characterized. To determine the domain(s) of LukE that are critical for DARC binding, we studied the hemolytic function of LukE–LukS-PV chimeras, in which areas of sequence divergence (divergence regions, or DRs) were swapped between the toxins. We found that two regions of LukE's rim domain contribute to hemolysis, namely residues 57–75 (DR1) and residues 182–196 (DR4). Interestingly, LukE DR1 is sufficient to render LukS-PV capable of DARC binding and hemolysis. Further, LukE, by binding DARC through DR1, promotes the recruitment of LukD to erythrocytes, likely by facilitating LukED oligomer formation. Finally, we show that LukE targets murine Darc through DR1 in vivo to cause host lethality. These findings expand our biochemical understanding of the LukE–DARC interaction and the role that this toxin-receptor pair plays in S. aureus pathophysiology.

HIV Type 1 (HIV-1) and simian immunodeficiency virus (SIV) display differential replication kinetics in macrophages. This is because high expression levels of the active host deoxynucleotide triphosphohydrolase sterile α motif domain and histidine-aspartate domain–containing protein 1 (SAMHD1) deplete intracellular dNTPs, which restrict HIV-1 reverse transcription, and result in a restrictive infection in this myeloid cell type. Some SIVs overcome SAMHD1 restriction using viral protein X (Vpx), a viral accessory protein that induces proteasomal degradation of SAMHD1, increasing cellular dNTP concentrations and enabling efficient proviral DNA synthesis. We previously reported that SAMHD1-noncounteracting lentiviruses may have evolved to harbor RT proteins that efficiently polymerize DNA, even at low dNTP concentrations, to circumvent SAMHD1 restriction. Here we investigated whether RTs from SIVmac239 virus lacking a Vpx protein evolve during in vivo infection to more efficiently synthesize DNA at the low dNTP concentrations found in macrophages. Sequence analysis of RTs cloned from Vpx (+) and Vpx (−) SIVmac239–infected animals revealed that Vpx (−) RTs contained more extensive mutations than Vpx (+) RTs. Although the amino acid substitutions were dispersed indiscriminately across the protein, steady-state and pre-steady-state analysis demonstrated that selected SIVmac239 Vpx (−) RTs are characterized by higher catalytic efficiency and incorporation efficiency values than RTs cloned from SIVmac239 Vpx (+) infections. Overall, this study supports the possibility that the loss of Vpx may generate in vivo SIVmac239 RT variants that can counteract the limited availability of dNTP substrate in macrophages.

Candida albicans and Aspergillus fumigatus are dangerous fungal pathogens with high morbidity and mortality, particularly in immunocompromised patients. Innate immune-mediated programmed cell death (pyroptosis, apoptosis, necroptosis) is an integral part of host defense against pathogens. Inflammasomes, which are canonically formed upstream of pyroptosis, have been characterized as key mediators of fungal sensing and drivers of proinflammatory responses. However, the specific cell death pathways and key upstream sensors activated in the context of Candida and Aspergillus infections are unknown. Here, we report that C. albicans and A. fumigatus infection induced inflammatory programmed cell death in the form of pyroptosis, apoptosis, and necroptosis (PANoptosis). Further, we identified the innate immune sensor Z-DNA binding protein 1 (ZBP1) as the apical sensor of fungal infection responsible for activating the inflammasome/pyroptosis, apoptosis, and necroptosis. The Zα2 domain of ZBP1 was required to promote this inflammasome activation and PANoptosis. Overall, our results demonstrate that C. albicans and A. fumigatus induce PANoptosis and that ZBP1 plays a vital role in inflammasome activation and PANoptosis in response to fungal pathogens.

Lys234 is one of the residues present in class A β-lactamases that is under selective pressure due to antibiotic use. Located adjacent to proton shuttle residue Ser130, it is suggested to play a role in proton transfer during catalysis of the antibiotics. The mechanism underpinning how substitutions in this position modulate inhibitor efficiency and substrate specificity leading to drug resistance is unclear. The K234R substitution identified in several inhibitor-resistant β-lactamase variants is associated with decreased potency of the inhibitor clavulanic acid, which is used in combination with amoxicillin to overcome β-lactamase–mediated antibiotic resistance. Here we show that for CTX-M-14 β-lactamase, whereas Lys234 is required for hydrolysis of cephalosporins such as cefotaxime, either lysine or arginine is sufficient for hydrolysis of ampicillin. Further, by determining the acylation and deacylation rates for cefotaxime hydrolysis, we show that both rates are fast, and neither is rate-limiting. The K234R substitution causes a 1500-fold decrease in the cefotaxime acylation rate but a 5-fold increase in kcat for ampicillin, suggesting that the K234R enzyme is a good penicillinase but a poor cephalosporinase due to slow acylation. Structural results suggest that the slow acylation by the K234R enzyme is due to a conformational change in Ser130, and this change also leads to decreased inhibition potency of clavulanic acid. Because other inhibitor resistance mutations also act through changes at Ser130 and such changes drastically reduce cephalosporin but not penicillin hydrolysis, we suggest that clavulanic acid paired with an oxyimino-cephalosporin rather than penicillin would impede the evolution of resistance.

The aftermath: Navigating a Taliban-led Afghanistan Expert comment NCapeling 20 August 2021

In the coming weeks, governments and international organizations must work through an approach to the Taliban takeover of Afghanistan. It will not be simple.

A failure to acknowledge that the legitimate, elected representatives of Afghanistan are no longer in control of territory or institutions, and to refuse to deal with those that are, will only make for further misery for a population which has already endured decades of violence and poverty.

But to recognize the Taliban risks condemning tens of thousands of Afghan women, children, and men to brutal repression and, for some, potential death, as well as mocking the human rights and rule of law which the US and its allies sought to promote in Afghanistan, and globally, as cornerstones of values-based foreign policies.

The dilemma western governments find themselves in is one they have studiously sought to avoid despite mounting evidence that, without a negotiated deal, a Taliban takeover was only a matter of time. As late as 6 August, the UN Security Council refused to countenance appeals by the UN mission and Afghan civil society activists to press the Taliban and the government to negotiate a ceasefire.

The US reiterated its refrain that it ‘will not accept a military takeover of Afghanistan’ and the UK stressed the Taliban’s only route to power was through meaningful engagement in a peace process. Meanwhile, not until 11 August did Germany and the Netherlands stop deporting Afghan migrants despite the pleas of Afghan authorities and refugee organizations that the country was on the brink of crisis.

Delaying the inevitable

Belief that a military takeover was still some months away may have led diplomats to view dealing with the Taliban as a distant task. The unilateral nature of the US deal with the Taliban and the resistance of the Ghani government to any suggestion of power-sharing arrangements compounded a lack of international coordination and planning on what the conditions for engagement might be.

It cannot be delayed further. The scale of the humanitarian crisis in Afghanistan is daunting, with more than half a million displaced by fighting in 2021 alone, almost 17 million facing crisis levels of food insecurity, and nearly half of all children under five malnourished as a consequence of drought and the COVID-19 pandemic.

With one of the highest global refugee populations and an estimated up 20-30,000 Afghans fleeing the country weekly – even before the government collapsed – Afghanistan evokes still raw memories of the 2015 Syria migrant crisis for Europe. Pakistan and Turkey, home to some of the largest Afghan refugee communities, have already closed their borders to more.

The ongoing chaos at Kabul airport highlights the challenges ahead. But there is a small window – before the UN Security Council is scheduled to review the mandate of the UN mission in Afghanistan by 17 September – for the US and its allies to craft an approach to dealing with the Taliban.

Formal recognition of a Taliban-led government is simply not an option, even for those maintaining a diplomatic presence in Kabul such as China, Iran, Pakistan, and Russia. Technically the Afghan republic has not yet dissolved with vice-president Amrullah Saleh, reportedly in hiding in the Panjshir valley, claiming he is the country’s ‘caretaker’ president.

Conditions for international acceptance

Afghanistan’s ‘enduring partners’ must now focus on building a consensus around five conditions for international acceptance of a Taliban-administered Afghanistan and prevent the Taliban again reaping the benefits of international divisions. The G7 began to articulate some of these conditions but they need to be set out and negotiated with Afghanistan’s neighbours before being formally articulated by the UN Security Council.

1. Adherence to Afghanistan’s human rights obligations. This must specify the rights of women and girls to education and work, the protection of ethnic and religious minorities, and safe passage for all Afghans and internationals leaving the country.
2. Amnesty for all individuals who worked for the Afghan government or international embassies, forces, or aid organizations since 2001.
3. No harbouring of terrorist groups. This has been the central condition for the US deal with the Taliban, and the overriding concern for both China and Russia.
4. Non-lethal public order. The provision of public order to enable supply routes to open, evacuations to continue, and aid to be delivered, is essential and one that Russia has made as a condition for its future relations.
5. Negotiation of inclusive political arrangements with Afghanistan’s political and ethnic factions.

The UN mission in Afghanistan, including its human rights component, and the Al-Qaida Sanctions Committee’s Analytical Support and Sanctions Monitoring Team should be mandated with reporting monthly on the progress toward these five conditions. Their assessments should form the basis for any reconsideration of the Taliban’s status as a terrorist organization. And a negotiated political settlement must be a precondition to the release of the government’s foreign reserves, estimated to be $9.5 billion.

Before this, the humanitarian and development aid on which Afghanistan is almost completely reliant must be recalibrated to flow through international agencies. Models such as Hamas-run Gaza, Assad’s Syria, or Aristide’s Haiti, show that while far from effective, it is possible to provide urgent assistance outside government channels.

This is one of the reasons why the Taliban has sought to retain a strong UN presence across Afghanistan and why the UN must be given a more significant political mandate and resources. The World Bank-administered Afghan Reconstruction Trust Fund should remain the principal channel for international funds.

It is difficult in the short-term to see the US leading this collective effort, given its defensive and domestic-focused position. It could be a moment for the UK and EU to demonstrate their multilateral commitments and forge a coordinated conditions-based approach to a Taliban-administered Afghanistan at the UN.

Going beyond handwringing or gesture politics will be difficult and messy and, ultimately, Afghanistan’s future must be decided by Afghans. Until that day, however, this will save lives.

Russia's end games and Putin's dilemmas Expert comment NCapeling 14 February 2022

As warnings from Washington and London intensify, the period of maximum danger in the Ukraine standoff has begun. Even if conflict is avoided, the status quo has gone.

There are several reasons to believe conflict over the Ukraine is imminent. The military build-up is complete. Russia has added tactical support elements, including medical units, to its already large and comprehensive array of troops and equipment deployed to the east, north, and south of Ukraine.

Additional naval units have entered the Black Sea, military exercises with Belarusian forces have begun and, along with those on Russian territory, these can all provide cover for an intervention of some sort.

Far from being comforting, comments by Vladimir Putin and his entourage that it will not be Russia provoking a conflict are ominous. Russian media has ramped up domestic programming about the ‘imminent Ukrainian fascist threat’ to the motherland. And a recent US intelligence briefing alleges sophisticated preparations by Russian intelligence include releasing a video of a staged attack on Russian-speaking civilians in northern Ukraine.

Should Russia attack, its ‘fortress economy’ could weather a new round of sanctions for several years, not least given the growth in Russia’s hard currency reserves to $630 billion, under 20 per cent of which are now held in US dollars, and the high demand for – and global price of – oil and gas.

What does Putin really want?

Diplomacy is in high gear but, as Putin and other senior Russian figures have made clear, the US and European offers of new security confidence-building measures do not address Russia’s two core, stated demands – namely to withdraw US and NATO forces close to its borders in former Soviet and Warsaw Pact states, and to end NATO’s ‘open door’ policy to future enlargement.

For the Kremlin, enlargement to Ukraine would remove a critical buffer between Russia and the NATO alliance. If Putin’s objective, therefore, was simply to put down an unambiguous marker that Ukrainian membership of NATO is a red line, he has made progress.

He has reminded the world and Ukraine’s leadership of that country’s strategic vulnerability. US president Joe Biden and his European counterparts have stated NATO will not commit forces to defend Ukraine if it is attacked. And although they remain resolute on the ‘open door’ policy, there have been reminders NATO does not accept new members who risk importing a pre-existing conflict into the alliance.

If another Putin objective was to refocus US and, to a lesser extent, European attention away from China and back onto Russia and its security interests, he has succeeded. NATO has offered some new confidence-building measures around the conduct of military exercises and deployment of forces, while the US may be willing to enter negotiations for a new treaty with Russia to limit nuclear missiles deployed in Europe.

This would mean setting aside the growing threat posed by Chinese missiles that had partly motivated the Donald Trump administration to withdraw unilaterally from the Intermediate-Range Nuclear Forces (INF) Treaty.

But there is another scenario to consider – that although these two issues are both important, neither are Putin’s core objective, which instead is to right once and for all the historical ‘wrong’ of Ukraine’s separation from Russia in 1991.

As Putin made clear in a lengthy essay in July 2021, he sees an independent, sovereign Ukraine as a historical aberration, and he blames the US for the deepening discord and animosity between ‘brotherly’ Ukraine and Russia.

Not stated in the essay is that the emergence of a more democratic and functional Ukraine poses an existential threat to Putin’s own control over Russia. In contrast, reincorporating Ukraine into a ‘greater Russia’ would underpin his now constitutionally-mandated opportunity to reign until 2036, as well as being his biggest legacy.

The problem is it seems impossible to bring Ukraine permanently back into Russia’s sphere of influence without some form of new military intervention.

Putin’s options

Putin’s strategy to date has been limited to ensuring the breakaway Ukrainian portions of Donetsk and Lugansk gain a legal right to block any future efforts by the central Ukrainian government to join either the European Union (EU) or NATO.

The Kremlin sees expansive interpretation and implementation of the 2014-15 Minsk protocols allowing self-governance for these areas currently under Russian military control as a potential route to this outcome. But for Volodomyr Zelensky or any future Ukrainian president to accept this would be political suicide, and Kyiv has already resisted French and German pressure to make this concession under the Normandy Format of meetings they share with Russia.

If Putin has now decided to undermine Ukrainian sovereignty more explicitly, he can order a limited military intervention further into these occupied territories – and perhaps areas adjacent to them and Crimea – under the pretext of ‘protecting’ Russian-speaking communities there.

This would be relatively easy to achieve and, combined with a blockade of Ukraine’s Black Sea ports, could successfully destabilize the government in Kyiv. But such steps would trigger international economic sanctions and drive Ukraine even further towards the West.

A 21st century ‘blitzkrieg’ to take Ukrainian territory as far as the Dnipro River including Kyiv and all points east, would come closer to achieving Putin’s territorial and historic legacy. And this is now a feasible option given Russia’s military superiority. But how easily Russia could then hold the territory and consolidate its political control would be doubtful, and these moves also bring high-risk, long-term economic and diplomatic costs to Russia and to him personally.

No return to the status quo

On balance, Russian military intervention in the coming days or weeks is still less rather than more likely. Putin may yet accept a new, visible, bilateral accommodation with the US on the future of European security.

Professor Sir Laurence Martin (1928-2022) News release NCapeling 3 May 2022

Professor Sir Laurence Martin, director of Chatham House from 1991-96, has died aged 93.

Professor Sir Laurence Martin was one of the UK’s leading experts on international security with a particular interest in nuclear strategy.

Before joining Chatham House, he was Professor of War Studies at King’s College, London and Vice Chancellor of Newcastle University. He was also appointed Deputy Lieutenant of Tyne and Wear as well as holding several distinguished professorships.

His most well-known work was Two-Edged Sword: Armed Forces in the Modern World which was also the subject of the BBC’s Reith Lectures he gave in 1981.

Sir Laurence led Chatham House as the world was entering the post-Cold War era, a time when international relations were in a state of flux which, as he wrote in International Affairs, provided grounds for optimism that ‘the objective conditions exist to eliminate violent and mutually harmful conflict at least between the major powers’.

Professor Martin worked hard to ensure the financial sustainability of the institute following the loss of core funding from the UK government in the 1980s. By modernizing its approach to fundraising, he was able to invest in a much-needed refurbishment of the House, as well as the institute’s first foray onto the internet.

This enabled Chatham House to communicate with new audiences beyond its members, event attendees, and readers of printed reports, The World Today magazine, and International Affairs journal. He paid particular attention to the need for the institute to communicate its ideas to those making policy as well as wider audiences.

In addition to strengthening the institute’s research, he was keen to continue engaging its members in discussions to develop a well- informed understanding of international affairs.

On the 75th anniversary of Chatham House in 1995, he wrote that its role was ’providing the evidence and, above all, encouraging the habit of mind, to facilitate prudent, if possible optimistic, but never utopian judgements about world affairs’. Today’s staff would agree this role remains at the heart of delivering the institute’s mission.

Selected works

• Two-Edged Sword: Armed Forces in the Modern World
• The Reith Lectures: The Two-Edged Sword
• British Foreign Policy: Challenges and Choices for the 21st Century

Mark Carney to chair Chatham House senior advisers News release NCapeling 17 May 2022

Former Bank of England Governor Mark Carney will succeed Sir John Major as chair of Chatham House’s Panel of Senior Advisers.

Chatham House is pleased to announce Mark Carney will succeed Sir John Major as chair of the institute’s Panel of Senior Advisers.

Chatham House senior advisers bring deep, first-hand experience of the policy and business worlds and use their experience, knowledge and networks to advise the institute’s research agenda and disseminate its policy ideas.

Mark Carney is currently United Nations (UN) Special Envoy on Climate Action and Finance, UK prime minister Boris Johnson’s special finance adviser on COP26, as well as vice chairman and head of transition investing at Brookfield Asset Management.

He served as Governor of the Bank of England between 2013 and 2020 and as Governor of the Bank of Canada between 2008 and 2013.

Robin Niblett, director and chief executive of Chatham House says: ‘We are delighted to benefit from Mark Carney’s wealth of experience at the highest levels of decision-making on international financial policy, crisis management, and sustainability.

‘His personal commitment to leveraging economic and finance policies to combat climate change aligns with a central plank of the institute’s mission to help governments and societies build a sustainable future.

‘I also want to thank Sir John Major for his invaluable advice and support through such a pivotal time in the institute’s history; we are delighted that he will retain an affiliation as a President Emeritus of Chatham House.’

Sir Nigel Sheinwald, chair of Chatham House, says: ‘Mark Carney is perfectly placed to lead the institute’s Panel of Senior Advisers and help ensure our research is focused on improving international relations in practical ways.

‘His experience and expertise will be of great value as the institute undertakes a leadership transition and welcomes Bronwen Maddox as its new director in the autumn.

‘The Chatham House council greatly appreciates Mark Carney’s engagement in our future success, as we do Sir John’s commitment to the institute these past thirteen years.’

Mark Carney says: ‘I have long respected Chatham House as one of the world’s leading independent institutes on international policy and am honoured to take up the reins from Sir John Major of chairing its eminent Panel of Senior Advisers. Alongside other members of the panel, I look forward to contributing to the relevance and impact of Chatham House’s important work.’

In addition to having been Governor of the Bank of England and the Bank of Canada, Mark Carney also chaired the Financial Stability Board from 2011 to 2018 and, in 2015, established the Task Force on Climate Related Financial Disclosures.

In 2021, he launched the Glasgow Financial Alliance for Net Zero, to unite net-zero financial sector-specific alliances from across the world into one industry-wide strategic alliance.

Chatham House established the Panel of Senior Advisers in 2009, under Sir John’s Major’s chairmanship, to support the institute in achieving its mission to build a sustainably secure, prosperous and just world.

Individually and collectively, members of the panel support the institute in achieving its mission by advising on new topics for debate, offering input to the institute’s research, contributing to its private and public meetings, and disseminating the institute’s ideas across their networks.

The panel does not have governance responsibilities, which reside fully with the Chatham House council.

The Platinum Jubilee of Her Majesty Queen Elizabeth II News release NCapeling 1 June 2022

The staff, associate fellows and Council of the Royal Institute of International Affairs at Chatham House send congratulations and warmest wishes to Her Majesty Queen Elizabeth II on the occasion of her momentous Platinum Jubilee.

As the Patron of the institute since her accession to the throne in 1952, HM The Queen has underpinned Chatham House’s independence for seven decades and thereby strengthened the impact of our work on the critical issues facing the world.

HM The Queen lent her personal support to the establishment of the annual Chatham House Prize in 2005 and has presented the award in person on behalf of the institute’s members on three occasions.

Among her other direct engagements with Chatham House, HM The Queen has helped us engage the next generation by supporting and then attending the launch of the Queen Elizabeth II Academy for Leadership in International Affairs in 2014, when she met the first intake of Academy fellows.

We are enormously grateful for her continued involvement as Patron of the institute and wish her and the Royal Family a memorable Platinum Jubilee.

Independent Thinking: Myanmar, the coup two years on Audio NCapeling 2 February 2023

Episode 13 of our weekly podcast focuses on the ongoing crisis in Myanmar, marking the two-year anniversary of the coup there by the Tatmadaw armed forces.

In February 2021 the Tatmadaw overthrew the democratically-elected government of Aung San Suu Kyi in Myanmar and, since then, the country has descended into a brutal and complex civil war.

Our panel analyses the state of the country and its people two years on. Can Myanmar hold together, can democracy ever be restored? And is the world ignoring a major humanitarian crisis in the making?

With Bronwen Maddox to discuss the issues are two journalists who have both covered Myanmar extensively. Sebastian Strangio is an author and the Southeast Asia editor at The Diplomat, and Ali Fowle is a freelance journalist with Al Jazeera and the BBC.

Joining them in the studio from Chatham House are Ben Bland, director of our Asia-Pacific programme, and Rashmin Sagoo, director of our International Law programme.

About Independent Thinking

A weekly podcast hosted by Chatham House director Bronwen Maddox, in conversation with leading policymakers, journalists, and Chatham House experts providing insight on the latest international issues.

Independent Thinking: Humanitarian disaster in Syria and Turkey Audio NCapeling 16 February 2023

Episode 15 of our weekly podcast examines the far-reaching consequences of the earthquakes which struck Turkey and Syria on the region’s fragile geopolitics.

With thousands killed and international aid flooding in, what hope is there for the many thousands of people in Syria and Turkey caught between the groups and governments involved in conflict for more than a decade.

The panel aslo discusses the political impact within Turkey, as fears grow that President Recep Tyap Erdogan may postpone the upcoming election amid outcries over corruption and the devastating loss of life.

Joining Bronwen this week is Lina Sinjab, Syrian filmmaker and BBC journalist covering the Middle East, Charles Lister, senior fellow and director of the Syria programme at the Middle East Institute, and Ziya Meral, senior associate fellow on Turkey at the Royal United Services Institute (RUSI).

About Independent Thinking

A weekly podcast hosted by Chatham House director Bronwen Maddox, in conversation with leading policymakers, journalists, and Chatham House experts providing insight on the latest international issues.

Synapse loss is associated with motor and cognitive decline in multiple neurodegenerative disorders, and the cellular redistribution of tau is related to synaptic impairment in tauopathies, such as Alzheimer's disease and frontotemporal dementia. Here, we examined the cellular distribution of tau protein species in human tau overexpressing line 66 mice, a transgenic mouse model akin to genetic variants of frontotemporal dementia. Line 66 mice express intracellular tau aggregates in multiple brain regions and exhibit sensorimotor and motor learning deficiencies. Using a series of anti-tau antibodies, we observed, histologically, that nonphosphorylated transgenic human tau is enriched in synapses, whereas phosphorylated tau accumulates predominantly in cell bodies and axons. Subcellular fractionation confirmed that human tau is highly enriched in insoluble cytosolic and synaptosomal fractions, whereas endogenous mouse tau is virtually absent from synapses. Cytosolic tau was resistant to solubilization with urea and Triton X-100, indicating the formation of larger tau aggregates. By contrast, synaptic tau was partially soluble after Triton X-100 treatment and most likely represents aggregates of smaller size. MS corroborated that synaptosomal tau is nonphosphorylated. Tau enriched in the synapse of line 66 mice, therefore, appears to be in an oligomeric and nonphosphorylated state, and one that could have a direct impact on cognitive function.

Alzheimer's disease (AD) is characterized by neuronal loss and accumulation of β-amyloid-protein (Aβ) in the brain parenchyma. Sleep impairment is associated with AD and affects about 25–40% of patients in the mild-to-moderate stages of the disease. Sleep deprivation leads to increased Aβ production; however, its mechanism remains largely unknown. We hypothesized that the increase in core body temperature induced by sleep deprivation may promote Aβ production. Here, we report temperature-dependent regulation of Aβ production. We found that an increase in temperature, from 37 °C to 39 °C, significantly increased Aβ production in amyloid precursor protein-overexpressing cells. We also found that high temperature (39 °C) significantly increased the expression levels of heat shock protein 90 (Hsp90) and the C-terminal fragment of presenilin 1 (PS1-CTF) and promoted γ-secretase complex formation. Interestingly, Hsp90 was associated with the components of the premature γ-secretase complex, anterior pharynx-defective-1 (APH-1), and nicastrin (NCT) but was not associated with PS1-CTF or presenilin enhancer-2. Hsp90 knockdown abolished the increased level of Aβ production and the increased formation of the γ-secretase complex at high temperature in culture. Furthermore, with in vivo experiments, we observed increases in the levels of Hsp90, PS1-CTF, NCT, and the γ-secretase complex in the cortex of mice housed at higher room temperature (30 °C) compared with those housed at standard room temperature (23 °C). Our results suggest that high temperature regulates Aβ production by modulating γ-secretase complex formation through the binding of Hsp90 to NCT/APH-1.

Grassroots to global: Young changemakers against violence 24 October 2024 — 3:00PM TO 4:00PM Anonymous (not verified) 11 October 2024 Chatham House

As part of Black History Month, this event will look at how youth activism against violence can influence change.

To address the alarming increase knife crime, a 10% rise in knife-related homicides between April 2022 and March 2023, the UK government launched a coalition of community leaders, campaigners and policy makers to tackle this tragic loss of life.

With people under 25 disproportionately affected, the ‘knife crime epidemic’ represents an example of how youth activist groups are central to tackling the problem. Organisations for and operated by young people form a key part of the strategy to ensure people are better protected from violent crime.

Around the world, a network of youth groups are similarly striving to make a difference and build a better life for future generations. Operating in different political and economic conditions, there are learnings to be found in groups working across the world.

This session will discuss how grassroot activism and youth organisations can influence governments to prevent young people falling into crime, the role of race and religion, and whether organisations are improving in their effectiveness around the world.

This event is a collaboration with Integrate UK.

Resetting Africa-Europe relations: From self-deception to economic transformation 28 October 2024 — 12:30PM TO 1:30PM Anonymous (not verified) 16 October 2024 Chatham House and Online

Experts assess the status of ties between Africa and Europe in a rapidly changing world, launching a new book that explores how misconceptions in the relationship can harm Africa’s economic agenda.

The relationship between Africa and Europe has long been shaped by colonial legacies, power imbalance and shifting geopolitical interests.

Almost three years on from the last EU-AU summit in Brussels in February 2022, questions remain over the delivery of headline commitments under the continent-to-continent partnership – ranging from the EU’s Global Gateway infrastructure strategy to wider climate financing promises.

As Africa seeks to strengthen its standing on the global stage, marked by the African Union’s upcoming debut at the G20 summit in November, a critical reassessment of these dynamics is needed to examine whether the continent’s relationship with Europe can overcome stigmatized narratives in search of genuine economic benefit.

At this event, which launches a new book by Professor Carlos Lopes: The Self-Deception Trap: Exploring the Economic Dimensions of Charity Dependency within Africa-Europe Relations, speakers assess the prospects for a transformative shift towards a more equitable and mutually beneficial Africa-Europe partnership.

Sinwar’s death does not make Hamas–Fatah reconciliation more likely, whoever his successor may be Expert comment jon.wallace 22 October 2024

The killing may aid Hamas recruitment – but it will not make agreement with Fatah any easier to achieve.

Western political leaders were quick to argue that Israel’s killing of Hamas leader Yahya Sinwar on 17 October presented an opportunity for a ceasefire in Gaza and the return of Israeli hostages.

US President Joe Biden immediately called on Israeli prime minister Benjamin Netanyahu to seize the moment to negotiate, now that Israel has achieved one of its war aims.

However, that ‘moment’ has already passed. Israel’s military assault on Gaza has intensified since Sinwar was killed, leading UN Peace Process Co-ordinator Tor Wennesland to say that ‘nowhere is safe in Gaza’. It is abundantly clear Netanyahu is intent on further degrading Hamas, resetting a new ‘power balance’ and carving out a buffer zone, no matter the cost in Palestinian lives or Israeli hostages. 

But there are other implications of Sinwar’s assassination beyond the zero-sum analysis of will there or won’t there be a ceasefire.

Hamas’s ability to fight

At present, everyone has an opinion on how Sinwar’s killing will affect Hamas and its ability to resist and respond to Israel’s military. His death will have been a major blow – symbolically, operationally, and psychologically. Hamas has been downgraded and its capacity to respond compromised.

But it will recover, regenerate and retaliate in time – and Sinwar’s death will have been no surprise to Palestinians in Gaza or elsewhere. Hamas is accustomed to seeing its leaders assassinated. Since its formation in 1987, it has been ‘decapitated’ many times, only to continue with its mission to ‘liberate Palestine’.

Hamas’s portrayal of Sinwar dying in his fatigues, head wrapped in a keffiyeh and resisting until the end will persuade many young Palestinians that he died as a martyr serving the Palestinian cause. Many will be inspired to join and fortify the ranks of Hamas as a result.

The IDF’s release of drone footage showing Sinwar’s last moments will have done nothing to undermine his credibility. 

On the contrary, it will serve as a rallying call to disaffected and disenfranchised young Palestinians horrified by Israel’s bombing of civilian targets in Gaza and disaffected with Fatah’s inability to prevent Israeli settler expansion and violence in the West Bank.

Reconciliation

Some hope that if Sinwar is replaced by a more ‘moderate’ leader, his killing may smooth the path to Hamas–Fatah reconciliation – and that this could provide a foundation for a patchwork political solution when Israel and Gaza arrive at the ‘day after.’  

But the idea that a downgraded and ‘leaderless’ Hamas will be susceptible to international pressure to reconcile with Fatah is divorced from reality.  

Prospective new Hamas leaders such as Khaled al Meshaal and Khalil al-Hayya are based in Qatar. 

They may be more pliable to external pressure to reconcile with Fatah in search of a political outcome, but their ability to influence events on the ground in Gaza will be limited. That was demonstrated by the Sinwar-orchestrated attacks on 7 October 2023, which took place without the blessing of the exiled leadership in Doha.

Hamas has long gone to ground in Gaza and become far more decentralized than it was before 7 October. It is now more typical of an insurgency, where Hamas cadres exercise a great degree of operational autonomy.

In other words, the disconnect between Hamas in Gaza and its political leadership in Qatar has only grown wider since this round of conflict started.

International efforts

That will undermine international efforts made by Qatar, Egypt, Saudi Arabia, China, Russia and others to bring about a reconciliation. Moscow and Beijing already hosted reconciliation talks in February and April early this year but made no progress in closing the chasm between the two parties. Saudi Arabia has also hosted talks.

The three Arab states, none of which have so far commented publicly on Sinwar’s killing, will likely view his death as an opportunity to bolster the political wing of Hamas – backing it with pledges of political, diplomatic and financial support.

Saudi Arabia and Egypt will have next to no influence over the succession process, but Qatar’s long-established relationship with the political wing of Hamas affords it leverage over the organization, albeit limited. They may be able to strengthen the hand of those based in Doha by promising to work harder at securing a ceasefire, guaranteeing the provision of humanitarian relief, and working towards a political solution.

In conversation with James Manyika, Senior Vice President of Research, Technology and Society at Google 12 December 2024 — 11:15AM TO 12:45PM Anonymous (not verified) 29 October 2024 Chatham House and Online

A conversation on AI’s global, societal and economic impacts.

2024 has been a landmark year for Artificial Intelligence (AI) development, deployment and use, with significant progress in AI-driven science, governance and cooperation. Looking ahead, AI continues to demonstrate economic promise and potential to expand on scientific breakthroughs in areas such as climate and health. This wave of innovation is occurring against a backdrop of geopolitical uncertainty and not all countries are fully able to participate. Heading into 2025, there are urgent questions about how best to maximise shared opportunities when it comes to AI and to advance global cooperation.

James Manyika, Senior Vice President of Research, Technology & Society at Google, will unpack what 2025 will bring for AI in science, economics, global governance and international cooperation. 

Key questions include:

• What will be AI’s global societal and economic impact in 2025 and beyond? 
• What are the ways AI could help increase economic growth and economy-wide productivity? What factors must be in place for this to happen?
• How best can we maximise shared opportunities and advance global cooperation when it comes to AI? Where can public-private partnerships unlock scientific breakthroughs for societal progress, combatting shared global challenges such as climate change and global health issues?  
• What are the principles of safe, responsible AI, and how should companies remain responsive to their evolution and integrate them into technology design and implementation? 
• What is the current – and ideal – role of technology companies in emerging mechanisms for global cooperation and national governance on AI?

This event is being held in partnership with Google.

You will receive notice by 13:00 on Wednesday 11 December if you have been successful in securing an in-person place.

The institute occupies a position of respect and trust, and is committed to fostering inclusive dialogue at all events. Event attendees are expected to uphold this by adhering to our code of conduct.

Harris and Trump's shared goal masks a fundamental AI policy divide Expert comment rgold.drupal 3 November 2024

Both presidential candidates will pursue US tech dominance but differ on the means to achieve it.

There remain some differences between the US presidential candidates’ positions on the governance of artificial intelligence and other emerging technology, notably around competition. 

But under either future administration, US decision-making looks set to be heavily influenced by growing securitization, the aims of the US technology industry and broader competition with China. 

‘Safe’ AI development 

Vice President Kamala Harris attended the inaugural Global AI Safety summit in the UK in 2023, where she announced President Joe Biden’s Executive Order on AI. This significant move by the federal government sought to define national and cyber security guidelines for AI developers and outline privacy and transparency guarantees. It also committed the federal government to a review of the National Security implications of this emerging technology, which was published last week.

In her remarks at the summit, Harris was clear that her definitions of safety extended beyond catastrophic risk mitigation to societal and personal harm. She noted the corrosive effects of some algorithmic decision-making and disinformation on democracy, appealing for AI that is developed ‘in the service of the public interest’.

A number of initiatives developed during the Biden administration have attempted to steer emerging technology as it takes root in society. This includes the establishment of the US AI Safety Institute, various schemes on global AI governance and investment in Public AI projects like the National AI Research Resource (NAIRR).

The US public is largely supportive: polling by the AI Policy Institute (AIPI) points to a majority preference for safety standards governing the US effort to lead in AI, rather than pedal-to-the-metal development. Investment in public options on AI and the infrastructure required to develop and sustain it is a bold direction that the incoming administration should consider expanding.

Biden’s Executive Order on AI has come under fire by the Trump campaign. At a rally in Iowa, Trump explained that he would cancel the order ‘on day one’, echoing a Republican platform that described it as imposing ‘Radical Leftwing ideas’ . 

Trump does, however, have his own track record in technology policy. During his first presidency, his administration passed an Executive Order on AI, stressing that ‘continued American leadership in Artificial Intelligence is of paramount importance to maintaining the economic and national security of the United States’. The tools and institutions announced as part of the order – including AI research investment, national AI research institutes and AI regulatory guidance including on federal use of AI – echo those of the current administration. 

Four years is a long time in AI, however. As the power of this technology is revealed, talk of safety may give way to talk of security. While the candidates may disagree on the role of the federal government in setting standards, there will be close alignment on the central need for US supremacy in national security. Neither administration seems likely to erect barriers to securitization of AI should it emerge as a critical strategic asset.

AI regulation at home 

American industry will remain the pivotal force shaping the US AI ecosystem, particularly as America jostles for position as the maker of the global rules governing AI. A notable aspect of Biden’s AI Executive Order was where it staked responsibility. Reports by AI and Cloud companies on the safety of their tools and infrastructure are sent to the Department of Commerce.

Under Secretary Gina Raimondo, whose star continues to rise, the department has become significantly more engaged with technology companies. In the absence of any other legal authority, AI governance has therefore sat under the purview of a secretary who herself has noted that they are ‘not a regulator’. 

The trend of industry leaders driving the government agenda on AI is replicated in other departments. There was an outcry over the composition of the new Department of Homeland Security advisory panel, the Artificial Intelligence and Security Board, with civil society groups concerned about the preponderance of industry voices: the 22-member panel includes the CEOs of OpenAI, Anthropic, NVIDIA, IBM, AWS, Adobe, Microsoft and Alphabet.

Under a Harris presidency, these trends seem likely to continue. Plus with deadlock in Congress probable, establishing new legal authorities for emerging technology will be difficult. That will likely mean emerging tech governance remains heavily influenced by the Department for Commerce. 

Like Harris, Trump has his allies in industry. While the Biden administration has courted the CEOs of AI companies who have historically spoken out in favour of regulation, Trump’s allies tend towards a more deregulatory agenda. 

Silicon Valley billionaires Elon Musk and Marc Andreessen have backed Trump’s plans to minimize AI regulation, lauding his support for ‘little tech’. They have also backed reported plans for so-called ‘Manhattan Projects’ to develop military technology, stewarded by ‘industry-led’ agencies. Trump’s aversion to strong regulatory institutions may mean an end to Biden’s anti-trust efforts, benefitting the biggest voices in the room, though his VP pick may disagree. JD Vance has somewhat surprisingly come out strongly in defence of the current chair of the Federal Trade Commission, Lina Khan, and her anti-trust efforts targeting US big tech.

Regardless, business interests will likely shape either a Harris or Trump administration’s approach as the US grapples with balancing the ambitions of its industry with an increasingly protectionist stance towards its biggest import market, China.

Competition abroad

China looms large in the imaginations of both campaigns. 

The US has signalled to its allies that American AI standards should replace Chinese standards. Export controls on semiconductors were expanded in September this year, with key voices in the industry – notably the Netherlands, Japan and South Korea – describing the restrictions as ‘economically motivated’ despite nominally being tied to national security by the US. 

The UK needs to address growth and debt problems if it is to match resources to ambitions on international priorities Expert comment LJefferson 5 November 2024

The budget marks the lowest amount in decades the country has spent on development, and it is struggling to fund other international priorities too.

The UK’s Chancellor Rachel Reeves unveiled her much-anticipated budget last week, the first of the new Labour government. Labour is in a difficult place. There are numerous calls on the public purse and public services are not performing well. Meanwhile, public debt remains close to 100 per cent of GDP, and there has been a long run of sluggish growth.
 
Reeves argues with some justification that the previous government left her a challenging inheritance – gaps in this year’s spending plans, and persistent debt questions left unresolved. More importantly, there are longer-term concerns about the sustainability of UK public spending – the country’s Office for Budget Responsibility has warned public debt could triple by the 2070s due to an ageing population, the climate crisis, and security risks. The focus has understandably been on kitchen table questions about tax rises and funding public services.
 
But this picture also has longstanding implications for international policy – on whether the UK can afford to invest in its foreign policy. The Chancellor did announce an increase of £2.9bn for defence. But the question of whether the UK can get on a sustainable path to spending 2.5 per cent of GDP on defence is still being worked through in the ongoing Strategic Review, and remains challenging despite increasingly urgent warnings from parliamentary committees about the UK’s defence readiness.

The budget also marks one of the lowest amounts in recent years the UK will spend on development overseas, despite setting an ambition to reset relations with the Global South and recover the UK’s role as a leader in international development.
  
The UK needs to either match resources to ambition, spend much more efficiently, or, in the case of the aid budget, it could seek to focus on priorities that are less dependent on spending. But even this will still require consistent resources, alongside significant diplomatic attention, intellectual leadership, and focus.

Longer-term, the UK may need to consider larger questions: addressing broader problems with its lack of growth and productivity will be critical to fund an expansive international role.

With this budget, UK aid spent overseas is at a historic low

In 2020 the UK government cut its goal for spending on international development to 0.5 per cent of Gross National Income (GNI), ending a longstanding policy of spending 0.7 per cent. Labour have echoed this, promising to only return to previous levels when fiscal circumstances allow.
 
But this masks a bigger issue. Since 2022, significant amounts of the UK’s aid budget have been spent on accommodation for asylum seekers in the UK. This is within the rules governing aid, but reduces the amount spent on reducing poverty overseas. In 2023 this spending was 28 per cent of the £15.4bn aid budget. In 2016, it was 3.2 per cent. 

Previous Chancellor Jeremy Hunt quietly allowed a top-up of aid spending over the last two fiscal years to offset how much is being spent at home on asylum seeker accommodation. That provided an additional £2.5 billion for 2022–23 and 2023–24.

But Rachel Reeves declined to provide extra funding this time, meaning the amount being spent overseas is likely the lowest its been since 2007 – an effective cut – under a Labour government.

The Minister for Development, Anneliese Dodds, speaking at Chatham House last month, said the government is working on clearing the backlog of asylum claims, which should free up more to spend overseas.

But beyond this there has been little clarity on plans to address the issue. And costs for asylum seeker accommodation have increased significantly – the UK appears to spend much more than comparator countries per head, according to the Center for Global Development, raising questions about how this spending is managed.

Development is not just about money – but money is important

The UK debate about development has often focused on the 0.7 per cent figure, which can distract from larger questions about what development policy is intended to achieve. As many experts have argued, development aid is about more than spending, and the wider, complex process by which the UK contributes to broad-based growth and stability for poorer countries is not about hitting a specific number.
 
There are things the UK can do that aren’t about spending more directly. This might include focusing on priorities like reforming multilateral development banks so they provide more low-cost public finance, and more flexible and agile loans to poorer countries – a priority echoed by Dodds. It might also incorporate focusing more broadly on helping developing countries attract more investment to bolster growth. 

There is also the issue of developing country debt, much of which is held by the private sector. Dodds previously said, when she was shadow chancellor, she might consider changing the law to address this issue. However,  she declined to recommit to this when questioned at Chatham House. 

None of this can be done unilaterally – on debt, for example, the UK has spearheaded some creative policies. Its UK Export Finance body developed climate-resilient debt clauses – agreements that countries can pause debt repayments in the event of a climate shock – but the UK holds limited amounts of developing country debt. Impact will only come by galvanizing and coordinating others to adopt similar approaches.

Members’ Christmas drinks 11 December 2024 — 6:00PM TO 8:00PM Anonymous (not verified) 11 November 2024 Chatham House

Join us at 10 St James’s Square for a chance to raise a glass with fellow Chatham House members and staff.

This evening is a special opportunity to meet fellow Chatham House members and staff around the Christmas tree.

Please note this reception is open to members of Chatham House only. Regrettably, we are unable to register non-member guests.

The institute occupies a position of respect and trust, and is committed to fostering inclusive dialogue at all events. Event attendees are expected to uphold this by adhering to our code of conduct.

The break-up of Scholz’s coalition government signals the end of Germany’s old economic model Expert comment jon.wallace 12 November 2024

The coalition could not agree how to fund new support for Ukraine and failed to fully implement the ‘Zeitenwende’. A new government must push through reform.

As Europeans were still processing Donald Trump’s victory in the 2024 US presidential election, an acrimonious break up occurred 4000 miles east of Washington DC.

Reports had been circulating for weeks about the fragile state of Germany’s ‘traffic light’ coalition government led by German Chancellor Olaf Scholz, consisting of the centre-left Social Democratic Party (SPD), the Green Party, and liberal Free Democratic Party (FDP).

The expectation had been that the coalition would hold on for a few more weeks and might even be given a new lease of life by Trump’s re-election. Instead, it collapsed on the day Trump’s win was confirmed. An unusually angry Scholtz announced in a live address that he had fired FDP Finance Minister Christian Lindner, effectively breaking up the coalition.

At the heart of the dispute was the so-called ‘debt brake’ – a constitutional mechanism which restricts Germany’s annual public deficit to 0.35 per cent of GDP. Lindner proposed a set of reforms which were unpalatable to the SPD and the Greens. 

In response, Scholz suggested declaring an emergency, which would have suspended the debt brake. That in turn was unacceptable to Lindner, leading to his sacking by the Chancellor.

Practically, this means the SPD and the Greens are now in a minority coalition, without agreement on the 2025 budget or the votes in parliament to pass it. They also still face the challenge of the debt brake.

A vote of confidence will take place in December, with elections to be held before the end of February 2025 latest.

The end of Germany’s economic model

At the root of Germany’s political crisis is the country’s economic model. For decades, Germany relied on a system that depended on cheap Russian gas, cheap imports of consumer goods from China, high-value exports – particularly in the automotive sector – and the US security umbrella.

With Russian energy no longer viable, the global economic landscape shifting, and Donald Trump on his way back to the White House, that model is no longer workable. And Germany’s economy is expected to contract by 0.2 per cent in 2024 – a contraction for the second year running.

The ‘Zeitenwende’, announced by Scholz in the wake of Russia’s full-scale invasion of Ukraine, should have signalled a turnaround of both foreign and economic policy, given how much the two are interconnected. Yet on both fronts, too little changed.

Germany’s reliance on Russian gas did come to an abrupt end in 2022. And Germany is Ukraine’s second largest military aid donor after the US, while accepting the most Ukrainian refugees.

But the ‘Zeitenwende’ turnaround ended there. Scholz’s coalition government failed to prepare for long-term investment in defence at the levels required by creating an off-budget defence spending fund which would have run out in 2027. The draft budget for 2025 showed defence spending would have been cut, as would support for Ukraine.

Germany has also struggled to turn around its economic woes, with the car industry particularly affected. Cheap Chinese EVs and new energy technologies are competing with Germany’s most powerful companies. Volkswagen, the country’s largest car manufacturer, has announced plant closures and layoffs due to shrinking profit margins.  

To the west, Trump’s threat to impose 10 to 20 per cent tariffs on all EU imports meant share prices of Volkswagen, BMW, Mercedez-Benz and Porsche all dropped between 4 to 7 per cent following news of his re-election.

To the east, trade tensions between the EU and China are intensifying. Yet rather than choosing to diversify, German companies have doubled down on their bets in China, with German investment in the country rising from €6.5bn for the whole of 2023 to €7.3bn in the first half of 2024 alone – only exposing carmakers further.

Germany’s support for Ukraine

Like French President Emmanuel Macron, Scholz had already been weakened by the results of the European Parliamentary elections in June. With the collapse of his traffic light coalition, the EU’s Franco-German ‘engine’ is now well and truly stalled – until new leadership can be found. This weakness comes at a perilous moment when clear, united European leadership, and much increased funding, is needed to shore up support for Ukraine.