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Toni Annala, Marc Hoyois and Ryomei Iwasa
J. Amer. Math. Soc. 38 (), 243-289.
Abstract, references and article information

Marcelo Campos, Matthew Jenssen, Marcus Michelen and Julian Sahasrabudhe
J. Amer. Math. Soc. 38 (), 179-224.
Abstract, references and article information

Nonphotochemical quenching (NPQ) is a mechanism of regulating light harvesting that protects the photosynthetic apparatus from photodamage by dissipating excess absorbed excitation energy as heat. In higher plants, the major light-harvesting antenna complex (LHCII) of photosystem (PS) II is directly involved in NPQ. The aggregation of LHCII is proposed to be involved in quenching. However, the lack of success in isolating native LHCII aggregates has limited the direct interrogation of this process. The isolation of LHCII in its native state from thylakoid membranes has been problematic because of the use of detergent, which tends to dissociate loosely bound proteins, and the abundance of pigment–protein complexes (e.g. PSI and PSII) embedded in the photosynthetic membrane, which hinders the preparation of aggregated LHCII. Here, we used a novel purification method employing detergent and amphipols to entrap LHCII in its natural states. To enrich the photosynthetic membrane with the major LHCII, we used Arabidopsis thaliana plants lacking the PSII minor antenna complexes (NoM), treated with lincomycin to inhibit the synthesis of PSI and PSII core proteins. Using sucrose density gradients, we succeeded in isolating the trimeric and aggregated forms of LHCII antenna. Violaxanthin- and zeaxanthin-enriched complexes were investigated in dark-adapted, NPQ, and dark recovery states. Zeaxanthin-enriched antenna complexes showed the greatest amount of aggregated LHCII. Notably, the amount of aggregated LHCII decreased upon relaxation of NPQ. Employing this novel preparative method, we obtained a direct evidence for the role of in vivo LHCII aggregation in NPQ.

A feminist and postcolonial approach to nuclear politics Expert comment NCapeling 20 July 2022

The July issue of International Affairs includes eight articles on the global nuclear order and eight more covering Chinese lending, abortion rights, and global security.

Disarmament and arms control has been a consistent area of debate in this journal for the past century, as underscored in our recent archive collection of research on a century of war and conflict.

The July edition moves this debate forward with a collection of papers guest-edited by Shine Choi and Catherine Eschle. The section ‘Feminist interrogations of global nuclear politics’ includes work by nine authors exploring seven global case-studies that help rethink nuclear politics and feminism.

As the guest editors note in their introduction, the section brings together research on nuclear power and nuclear weaponry to ‘begin the process of decentring 1980s white, western experiences of the global nuclear order in feminist IR’.

The articles speak to three core themes: they provide evidence of the ongoing destructive nature of nuclear technologies, extend understanding of the gendered, racialized, and colonial dimensions of nuclear discourses, and unearth the impact of colonialism on the global nuclear order.

Global nuclear politics

Anne Sisson Runyan examines the gendered effects of uranium mining and nuclear waste dumping on North American Indigenous women, showing how the nuclear cycle tends to have a disproportionate effect on certain communities but also that the area of disposal remains problematic.

This is a global problem – for example, the Royal Navy has yet to successfully dispose of a single redundant nuclear-powered submarine and is rapidly running out of space to store further vessels.

Hebatalla Taha goes back to the early years of nuclear development and, using Egypt as a case-study, her article argues the early visualizations of the atomic age were fluid and ambivalent. She concludes – perhaps controversially – that feminizing nuclear politics and nuclear images will not lead to disarmament but rather reinforce the nuclearized world. The piece is a welcome addition to the emerging field of visuality within international relations.

Anand Sreekumar brings together feminist and Gandhian thinking to suggest a way for Narendra Modi’s government to move beyond the possession of nuclear weapons as symbols of power. In doing so, he also critiques the binary labels of ‘West’ and ‘non-West’ that often frame our understanding of the world.

Lorraine Bayard de Volo revisits the Cuban missile crisis – a point in time where nuclear war looked likely. She compares the actions of Khrushchev, Castro, and Kennedy and finds the pursuit of masculinity led to the rejection of approaches considered more feminine, such as diplomacy and negotiation – the crisis was exacerbated by what might be referred to now as toxic masculinity.

Sweden’s and Finland’s recent application to join the nuclear alliance NATO lends a particular urgency to Emma Rosengren’s article on the original Swedish decision to renounce the development of nuclear weapons during the Cold War. Her article concludes much of the emphasis on power in international relations has contributed to a gendered and racialized nuclear order.

Similarly, Laura Rose Brown and Laura Considine’s article on the Non-Proliferation Treaty finds that ‘gender-sensitive’ approaches focus almost exclusively on women’s inclusion as opposed to feminist policy analysis. They end by making recommendations for future policymaking.

Finally, Rebecca Hogue and Anais Maurer look at the anti-nuclear poetry of Pacific women. This article raises fundamental questions about what is currently considered to constitute evidence. They point to the role of oral history in many communities and the tendency of policymakers and social scientists to ignore this source of understanding.

National politics with international implications

This edition’s ‘Editor’s Choice’ is Jeffrey A. Friedman’s article which questions whether US grand strategy is dead in a post-Trump world. Running counter to much of the existing literature, he suggests there is a strong bilateral commitment to existing partnerships and alliances within the US political establishment.

Following the US Supreme Court decision over Roe vs Wade, it is important to note the issue of abortion rights can have an international dimension. Megan Daigle, Deirdre N. Duffy, and Diana López Castañeda reveal that, although Colombia now has the most progressive legal framework for abortion in Latin America, intense backlash persists as legacies of the civil war overshadow the issue and lead to barriers to safe abortion care.

China

Ric Neo and Chen Xiang look at Chinese public opinion and finds that citizens can be upset by foreign policies of other states even when they have no impact on their daily lives. It reminds us of the potency of nationalism and the importance of who controls the prevailing narrative.

Deborah Brautigam examines China’s role in creating Zambia’s debt crisis, arguing this has not been brought about by a centralized master plan which would give China control over Zambia. Instead, the crisis has been caused by the failure of Chinese bureaucracy with too many state organs offering funding in an uncoordinated fashion.

Security and defence

Using Iran as a case-study, Henrik Stålhane Hiim argues the development of nuclear-capable ballistic missiles is a key indicator when looking for potential nuclear proliferators.

Eray Alim demonstrates the impact of an external great power interacting with local states. Russia’s involvement in the Syrian civil war has allowed it – sometimes through restrictive and punitive measures – to ensure Turkey and Israel do not harm its interests in the region.

Nina Wilén draws on fieldwork in Niger to study how Security Force Assistance (SFA) impacts on Niger’s security sector and compares this to global trends in security. She finds these developments contribute to blurred borders and confusion regarding labour division in the security sector and points to wider questions for intervenors in developing local units.

China’s political chessboard: The 20th party congress 14 October 2022 — 1:00PM TO 2:00PM Anonymous (not verified) 30 August 2022 Online

As the CCP gathers for its quinquennial political event, experts analyse its national, regional and global relevance.

In October, the Chinese Communist Party (CCP) assembles to appoint new leaders and discuss political, social, economic and foreign policy priorities for the coming 2022–2027 period and beyond.

One of the key outcomes of the meeting of China’s political class is the future of current President Xi Jinping. Technically, as he is at the end of his second five-year term, Xi was due to step down this year. The next generation of leadership was supposed to step in, as the next stage of the party’s evolution takes place.

However, this is unlikely to happen. The president has consolidated his power, manoeuvring allies into key positions and developing a faction of support in the party. With ‘Xi Jinping Thought’ added to the party charter and China’s constitution and term limits removed, Xi shows no intention of stepping down.

However, the president is not all-powerful. Critics and alternative factions operate within the party. His second term has also had to contend with the botched early handling of the pandemic, worsening ties with the US, and a slowing economy.

In an increasingly unpredictable world, events in the 2022 Party Congress will be hugely impactful for China’s and global affairs. What trajectory will Beijing take?

Key questions the panel discuss include:

• How does the Party Congress function and what does it mean for domestic Chinese politics?

• Will President Xi’s political and economic legacies continue under new political leaders and policymakers?

• What does President Xi’s next role in China’s government tell us about his power?

• As the 20th CCP Party Congress takes place, is there unity and cohesion at the top of the political structure?

• Will the Party Congress have any impact on China’s international relations? Particularly the US?

 As with all Chatham House member events, questions from members drive the conversation.

Read the transcript. 

The new geopolitics of nuclear power The World Today mhiggins.drupal 27 September 2022

States may be looking to build or restore nuclear plants, but they will need to bypass Chinese and Russian sector dominance, says Sung-Mi Kim.

Against the backdrop of a worldwide energy crisis, the global nuclear market may be seeing a renaissance with growing interest in nuclear energy.

Sceptics are being compelled to rethink the trade-off calculus of nuclear power for the first time since the 2011 Fukushima disaster, which prompted countries to postpone or phase out nuclear power. The nuclear option is again being seen as a way of boosting a nation’s energy autonomy and its ability to weather the volatility caused by unpredictable Russian gas supplies.

Adoption or expansion of nuclear energy capability will not allow a country to be free of Russian influence entirely given its dominant presence in the global nuclear sector. Rosatom, Russia’s state-controlled power corporation, and its subsidiaries, make Russia the leading exporter of nuclear power plants. Russia also supplies more than a third of the global fuel-related services, namely uranium conversion and enrichment. Notably, Russia has been capable of building these into an attractive financial package for importing countries, backed by generous state support.

Like Russia, Chinese government-owned nuclear corporations have started to make forays into export markets as part of its Belt and Road Initiative and ‘Go Out’ policy, which encourages companies to invest overseas. Both China and Russia have a strong comparative advantage in offering competitive state-backed financing schemes for nuclear products and services.

In the meantime, nuclear investment in advanced economies in the West have tended to remain stagnant. The International Energy Agency reports that of the 31 reactors built in the past five years, 27 are of Russian or Chinese design.

Given current market conditions and the technological complexity of the nuclear fuel cycle, new entrants will find it difficult to acquire energy autonomy through nuclear power. They will have to rely on foreign suppliers to build, operate and maintain their nuclear plants and supporting infrastructure. It typically takes a decade to build a nuclear plant and start generating electricity, and nuclear plant deals are built on a decades-long commitment of the parties to forge a political, technical, regulatory and scientific partnership that goes beyond purely commercial terms.

Nuclear export, therefore, is often a long-term, whole-of-the-government effort involving diplomatic skills and geopolitical calculations, and is subject to global oversight to ensure the peaceful use of nuclear energy.

The US is building strategic nuclear partnerships

In response to the Russian and Chinese dominance of the civilian nuclear sector, American nuclear industries are asking the government to streamline the export-licensing process and provide them with support. The US government is also establishing strategic partnerships with nuclear-capable allies such as South Korea to win procurement contracts. South Korea has recently made a U-turn in its nuclear policy. Its new president Yoon Suk-yeol intends to revive the role of nuclear power to help meet the country’s climate targets and has vowed to export 10 nuclear power plants by 2030.

In Japan, where nuclear energy production was halted after the Fukushima nuclear meltdown, a new policy platform was launched in 2019 to enhance public-private collaboration for nuclear research and development.

Intensifying geopolitical tensions between the US and its allies on one side, and Russia and China on the other, will inevitably affect nuclear market dynamics. Domestic economic slowdowns and international sanctions will be a stress test for the export potential of Russia and China.

For instance, in May 2022, Finland eliminated Rosatom from its consortium to build a nuclear power plant, citing delays and increased uncertainties stemming from the invasion of Ukraine. In 2020, Romania cancelled its nuclear deal with China, instead securing an agreement with the US to build two more reactors for its Cernavoda plant. The decision was seen as a move to align Romania with US intentions to sideline China.

 In March 2022, when the Czech Republic officially launched a tender to build a new reactor at the Dukovany nuclear plant, Rosatom and Chinese state-controlled nuclear exporter CGN have been excluded from the tender on security grounds.

As countries try to wean themselves off price-volatile gas and decarbonize their economies to meet climate targets, new commercial opportunities are opening up for the nuclear industry. At least 15 countries are building reactors, according to the World Nuclear Association. Some, such as China, are building more than one.

More than 30 countries are considering, planning or starting a nuclear programme. There is also a growing need for replacing or extending the lives of ageing reactors. It is in this context that the commercial, geopolitical and regulatory aspects of nuclear energy will play an increasing role in the  geopolitical contest for money and influence.

China Party Congress: Xi’s political blueprint The World Today rescobales.drupal 28 September 2022

In the second of her three-part series on the 20th National Congress of the Chinese Communist Party, Yu Jie outlines two key policy themes we can expect Xi to define: ‘common prosperity’ and ‘self-reliance’.

What can we expect from the Party Congress?

In mid-October five years ago, the 19th Party Congress opened with Xi Jinping delivering a political report lasting three-and-a-half hours. He will repeat the performance on October 16, the opening day of this year’s 20th Party congress.

Bland as its name may be, this political report is one of the Party Congress’s core items of business. It remains the most authoritative public account of the Chinese Communist Party’s path on all major policy fronts, containing a laundry list of policies undertaken by the outgoing Central Committee in the past five years, while putting forward guidance for future policy.

It represents the view of the current Politburo Standing Committee and that of the CCP. The 20th Congress report is a collegial effort and should not be considered Xi’s personal manifesto, nor should it be counted as another of his speeches to his comrades.

However, as general-secretary of the party for the past decade, it will most probably reflect many of the elements that Xi has influenced.

What are China’s political priorities?

No matter how complicated the geopolitics of the world becomes, Xi sticks to the conservative approach that has served his country well for past centuries: that China prioritizes the management of its own affairs.

Since the Cold War ended, two recurring themes have dominated the political report: the economy and security. For the 20th session, Xi will use the phrases ‘common prosperity’ as shorthand for the economy and ‘self-reliance’ for security.

Xi introduced the slogan ‘common prosperity’ at the start of his third term in August 2021. His aim was to close the income gap, address regional economic inequality and improve social welfare provision. Rebalancing social inequality was seen as essential to avoid the social disruption witnessed in other parts of the world.

Xi’s concept of ‘common prosperity’ was influenced by his childhood experiences living in exile in a remote village in Shanxi Province, in northwest China, during the Cultural Revolution. The ensuing upheaval was to prove a tragedy for his family and a disaster for the country.

His ambition is to define progress not in terms of producing double-digit growth but in dealing with the long-standing challenge of scarcities across different sections of society to meet ‘people’s ever-growing needs for a better life’. This direction was indicated at the 19th Party Congress by the term ‘shifting the principal contradiction’.

What state is the Chinese economy in?

Xi may have arrived at the right diagnosis but he has so far failed to find a cure that invokes ‘common prosperity’. After sweeping regulatory measures, the CCP has clamped down on its most successful private companies and spooked investors. While providing 80 per cent of China’s jobs, private enterprises are worried that the ‘common prosperity’ initiative may jeopardize their business.

Equally, Beijing’s zero-Covid policy has discouraged much-needed investment and failed to win the hearts and minds of Chinese youth, who have suffered most, both economically and socially.

The challenge facing Xi over the next five years will be to manage the financial risks in downsizing China’s property sector while coming out of a rigidly imposed Covid lockdown without reducing economic growth to such an extent that it damages the personal wealth of millions of people.

One hopes that Xi’s policies in future will be based on an innovative reading of the first-century phrase ‘seeking truth from facts’ adopted by Mao Zedong and last promoted as the political philosophy of Deng Xiaoping in the Seventies. A healthy market economy is not only essential for China’s development but as the only means of maintaining the party’s legitimacy, something vital for Xi.

Does China need more security?

China’s weakened export markets and less-friendly relations with the United States have encouraged it to become more self-reliant. Expect an emphasis on greater self-sufficiency in sectors of strategic importance to form a substantial part of this year’s political report.

In view of increased international hostility, Xi and his lieutenants have publicly recognized the need to take control of production and supply chains. These supply chains need to become ‘self-determined, self-controlled’ they have said, voicing frustration that the highest value-added elements of the Chinese tech sector remain reliant on overseas suppliers and vulnerable to geopolitical tensions.

Equally, on food and energy security, Russia’s invasion in Ukraine has exacerbated China’s already fragile food supplies as both countries are vital sources of food imports. Xi has already called for a ‘comprehensive thrift strategy’ to manage China’s food and energy needs.

Beijing is equally worried about the increase in oil and commodity prices which is driving up the cost of living. This may push parts of Chinese society out of ‘common prosperity’ and into ‘common poverty’, as it threatens to in some parts of Europe.

For the next five years, Xi needs to strike a balance between ‘common prosperity’ and ‘self-reliance’ to mitigate the storms ahead. He cannot afford to lockdown the world’s second largest economy indefinitely.

The hope is that the 20th Party congress will bring much-needed course corrections.

Read the two further articles in this series: the first provides a guide to why the Chinese Communist Party Congress matters; the third analyses the foreign policy issues likely to be discussed at the congress.  

Book preview: Guide to Chinese Climate Policy 2022 20 October 2022 — 10:00AM TO 11:15AM Anonymous (not verified) 28 September 2022 Chatham House and Online

Join authors David Sandalow and Michal Meidan to discuss their upcoming book.

China is the world’s largest emitter of greenhouse gases and a key player in tackling the global climate crisis. Its stated climate policies, namely its high-level targets to peak emissions by 2030 and to achieve carbon neutrality by 2060, are significant.

But while national-level ministries, local governments and businesses are setting climate roadmaps, implementation is challenging at times. In the current context of the global energy market and geopolitical turmoil, China’s need to maintain energy security can seem at odds with its climate pledges.

The authors will present the book, which examines Chinese emissions, the impacts of climate change in China, as well as China’s domestic and international climate change policies and the main implementation challenges these policies face.

China's Party Congress: a dose of foreign policy realism is needed The World Today mhiggins.drupal 11 October 2022

In the final article of three on the 20th Chinese Communist Party Congress, which opens on 16 October, Yu Jie argues that Beijing must show more pragmatism about Taiwan and the West.

How important is foreign policy at the congress?  

The political reports delivered to the delegates of the week-long 20th Chinese Communist Party Congress, which happens every five years, follow a Marxist-Leninist formula. Economics and the means of production form the base, while politics and society fill in the superstructure. 

We can expect sections on the work of the Chinese Communist Party (CCP), ideological discussion, economics, domestic politics, foreign affairs, cultural reform and social developments. Usually, the report prioritizes big domestic political issues.  

The political report typically sheds some light on the status of, and relationships between, senior party members. It can also provide insights into the political fortunes of various interest groups. The report acts as a summary of the party’s achievements and its plans – expressed as the lowest common denominator of consensus between competing factions. 

This year’s congress should be no different, and the political reshuffle that takes place is likely to signal how Beijing intends to rise to the many challenges at home and abroad. 

Given China’s growing power and its fraught relationship with the West, this year’s congress is expected to feature serious discussion on weighty foreign affairs issues affecting Beijing, and which will have long-lasting implications for the rest of the world.  

Which geopolitical issues will be priorities?  

When it comes to foreign affairs, China’s priorities rarely change. The CCP seeks to create a stable external environment to foster its domestic economic development. This conservative maxim was advocated in the 1980s by China’s then-paramount leader, Deng Xiaoping, and it will continue to guide Beijing’s relationships after this congress. 

While we don’t know the exact details of this year’s political report, we can expect discussion on relations with the US-led West, a possible shift in the relationship between Beijing and Moscow, and elaboration on China’s ties with the Global South.  

Notably, it’s likely that a separate chapter of the political report will see Taiwan treated alongside the special administrative regions of Hong Kong and Macau, signalling the party’s commitment to its claims over the contested island.  

Despite a chorus of nationalistic rhetoric surrounding the issue of Taiwan, Beijing will be careful not to stumble into an international conflict which risks causing colossal damage on all fronts. The choice of language on the so-called ‘Taiwan question’ in this political report will serve as a bellwether as to how, if at all, the party might fundamentally shift its views regarding Taiwan and deviate from the principle of ‘peaceful reunification’, the policy stated at every congress since 1979. 

How have China’s relations with the West worsened?  

President Richard Nixon’s visit to China in 1972, the first by an American president to the Communist nation, kicked off five decades of relative stability. However, as China’s global influence has grown, so have Washington’s fears.  

The relationship has transitioned from the cooperation and relative stability that existed under President George W. Bush and President Hu Jintao in the early 2000s, into one characterized by volatility and competition under Xi Jinping, Joe Biden and Donald Trump. These tensions are almost certain to continue in Xi’s likely third term. 

Elements of China’s relationship with the West, such as cooperation over military and aviation technology, are becoming far more competitive. At the same time, trade and investment, once viewed as strong ties, have been rapidly deteriorating – as seen, for example, by several major publicly listed Chinese state-owned enterprises and large private companies withdrawing from the New York Stock Exchange.  

Will Beijing stand by the Kremlin despite Russia’s invasion of Ukraine?  

At the same time, Beijing’s close relationship with Moscow and its lack of opposition to Russia’s war in Ukraine have put China in an awkward position. The CCP has realized that cooperation with its long-standing ally and neighbour must come with substantial limits to avoid undermining its own political priorities and interests.  

Russia’s recklessness may spur Xi and the CCP’s senior leadership to minimize the economic, financial and political risks associated with the Kremlin’s pursuit of war against a country aligned with, and supported by, the West.  

Will China continue to support its regional partners?  

On its ties with the Global South, Beijing began to rethink its Belt and Road Initiative (BRI) as the US-led Indo-Pacific strategy gained geopolitical momentum. Regions of Southeast Asia and South Asia received a lot of funding and resources for BRI projects, as seen with Chinese support for the China-Pakistan Economic Corridor.  

Xi also recently introduced the Global Development and Global Security initiatives, which the political report should flesh out. 

Beijing is fully aware that it can only prosper if its regional partners prosper, and it can only achieve resource security and border stability if its southern and western neighbours in Myanmar and Afghanistan cease to fight over land and resources. 

Chinese foreign policy over the last five years has been a strange combination of high-octane rhetoric and patient pragmatism. To respond to this contradiction, the congress could be used as an opportunity to inject a dose of realism.  

Read the two further articles in this series: the first is a guide to why the Chinese Communist Party Congress matters; the second discusses the key domestic policy themes that Xi Jinping is expected to outline at this year’s congress.

Climate justice with Chinese characteristics? Expert comment NCapeling 7 November 2022

China’s latest grand concept, the Global Development Initiative (GDI), claims to be making sustainability a key feature of the programme.

Since joining the World Trade Organization (WTO) in 2001, China has regularly unveiled a grand new strategic concept every four years or so.

Each has been deeply rooted in the Chinese political system and communicated via ambitious slogans, such as A Harmonious World, or New Types of Great Power Relations. And all have reliably generated both excitement and confusion abroad and within China.

China’s latest grand concept, the Global Development Initiative (GDI), is no exception. When Chinese president Xi Jinping introduced it at the United Nations General Assembly (UNGA) in September 2021, it made hardly any splash in the West, perhaps because China has already signalled its determination to shape international development in the post-COVID era.

But the GDI is more than just a new label for an ongoing project. One of its core political functions is to deflect some of the fierce criticism directed at its older sibling, the gigantic Belt and Road Initiative (BRI), which has a tarnished reputation for being neither transparent nor sufficiently ‘green’.

Focus on grants and capacity-building

According to the Chinese government’s initial description of the GDI, sustainability is a key feature of the programme. Unlike the BRI, the GDI will focus less on physical infrastructure projects – such as roads, bridges, digital networks, and coal-fired power plants – and more on sustainable-development grants and capacity-building.

In his remarks about GDI in 2021, Xi placed special emphasis on advancing the UN Sustainable Development Goals (SDGs) and helping developing countries manage the transition to a low-carbon economy.

On paper, then, the GDI appears a laudable initiative. While ongoing geopolitical tensions have deepened divisions between China and the US, derailing collaboration on combatting climate change, China at least is adjusting its diplomacy and aid programmes to position itself as a more attractive partner for those seeking climate security.

Since launching the GDI, it has already created the China-Pacific Island Countries Climate Action Cooperation Centre to help some of the world’s most vulnerable countries mitigate the damage from climate change.

But the GDI is still very much in line with China’s past grand initiatives. Its implementation is opaque and there is considerable flexibility in how it will deliver projects and offer grants. This approach is well understood and frequently practiced by Chinese political elites, following Deng Xiaoping’s famous reform ethos of ‘crossing the river by feeling the stones’.

Xi has clearly adopted this approach in introducing the GDI. But whereas Deng was steering China’s domestic economy during a period of isolation after the Cultural Revolution, Xi needs to involve many other countries in his vision. That will not be easy now that Russia’s war in Ukraine and other recent developments have complicated many of China’s international relationships.

China’s leaders recognize the BRI was not warmly received in global development circles, owing partly to its role in increasing both climate and financial risks. In implementing the GDI, they need to rethink some basic assumptions. Although gigantic infrastructure investments drove China’s own economic miracle, the same approach is not necessarily applicable everywhere.

Nor should China’s development aid be relentlessly used to seek diplomatic endorsement from other countries. Instead, producing a clear, concrete action plan with specific regional and thematic points of focus would enhance the GDI’s clarity and credibility.

Consider Xi’s recent pledge to add $1 billion to the $3.1 billion South-South Cooperation Assistance Fund, which will be renamed the Global Development and South-South Cooperation Fund. If China is serious about the GDI’s green credentials, this money should go towards supporting the clean-energy transition in response to the current oil and gas price crunch.

But the GDI’s success ultimately depends on how China deploys not just financial but political capital. It needs to show it can cooperate constructively with countries in the ‘GDI Friends Group’ launched at the UN in January 2022.

For many group members, the pandemic showed that existing development assistance programs urgently need to be updated to account for their recipients’ specific interests and priorities. After years of hollow diplomatic rhetoric, there is a craving for more meaningful assistance to help countries build resilience against climate-driven natural disasters and other growing threats.

China could help meet this demand, but it also will need to manage expectations. Many in the Global South assume a grand-concept policy such as the GDI will be meticulously planned from within Xi’s cabinet and thus executed to deliver large-scale, rapid results. But the GDI will require broad coordination across a wide range of ministries, agencies, and state-owned banks.

One party but not one voice

China may be ruled by one party, but that doesn’t mean its central administration system can always speak with one voice in supporting sustainable development abroad.

Since launching the BRI in 2013, China has showered the Global South with hundreds of billions of dollars in physical infrastructure investment. With the global climate debate increasingly focusing on the need to mobilize international financing for climate mitigation and adaptation in low and middle-income countries, many will be looking to both China and the advanced economies to provide the necessary support.

Russia and China in Antarctica: Implications for the Five Eyes 15 December 2022 — 11:00AM TO 12:00PM Anonymous (not verified) 2 December 2022 Online

This event explores Russia’s and China’s postions on the Antarctic and offers a critical assessment of their actions in the region.

Ever since the 1959 Antarctic Treaty System (ATS), signed at the height of Cold War, Antarctica has remained a demilitarized continent.

Today, even though the ATS is not in immediate danger of collapse, Antarctica and the Southern Ocean are no longer insulated from wider geopolitical tension, with China and Russia posing challenges to regional governance. 
 
This event also discusses key recommendations for the Five Eyes regarding Russian and Chinese current and future efforts at undermining the ATS and Antarctic governance. 

The discussion is informed by Mathieu Boulègue’s paper ‘Russia and China in Antarctica and the Southern Ocean: Implications for the Five Eyes’ published by the Sea Power Centre of the Royal Australian Navy.

An important mechanism of resistance to β-lactam antibiotics is via their β-lactamase–catalyzed hydrolysis. Recent work has shown that, in addition to the established hydrolysis products, the reaction of the class D nucleophilic serine β-lactamases (SBLs) with carbapenems also produces β-lactones. We report studies on the factors determining β-lactone formation by class D SBLs. We show that variations in hydrophobic residues at the active site of class D SBLs (i.e. Trp105, Val120, and Leu158, using OXA-48 numbering) impact on the relative levels of β-lactones and hydrolysis products formed. Some variants, i.e. the OXA-48 V120L and OXA-23 V128L variants, catalyze increased β-lactone formation compared with the WT enzymes. The results of kinetic and product studies reveal that variations of residues other than those directly involved in catalysis, including those arising from clinically observed mutations, can alter the reaction outcome of class D SBL catalysis. NMR studies show that some class D SBL variants catalyze formation of β-lactones from all clinically relevant carbapenems regardless of the presence or absence of a 1β-methyl substituent. Analysis of reported crystal structures for carbapenem-derived acyl-enzyme complexes reveals preferred conformations for hydrolysis and β-lactone formation. The observation of increased β-lactone formation by class D SBL variants, including the clinically observed carbapenemase OXA-48 V120L, supports the proposal that class D SBL-catalyzed rearrangement of β-lactams to β-lactones is important as a resistance mechanism.

Epoxide hydrolases (EHs) have been characterized and engineered as biocatalysts that convert epoxides to valuable chiral vicinal diol precursors of drugs and bioactive compounds. Nonetheless, the regioselectivity control of the epoxide ring opening by EHs remains challenging. Alp1U is an α/β-fold EH that exhibits poor regioselectivity in the epoxide hydrolysis of fluostatin C (compound 1) and produces a pair of stereoisomers. Herein, we established the absolute configuration of the two stereoisomeric products and determined the crystal structure of Alp1U. A Trp-186/Trp-187/Tyr-247 oxirane oxygen hole was identified in Alp1U that replaced the canonical Tyr/Tyr pair in α/β-EHs. Mutation of residues in the atypical oxirane oxygen hole of Alp1U improved the regioselectivity for epoxide hydrolysis on 1. The single site Y247F mutation led to highly regioselective (98%) attack at C-3 of 1, whereas the double mutation W187F/Y247F resulted in regioselective (94%) nucleophilic attack at C-2. Furthermore, single-crystal X-ray structures of the two regioselective Alp1U variants in complex with 1 were determined. These findings allowed insights into the reaction details of Alp1U and provided a new approach for engineering regioselective epoxide hydrolases.

The QT interval is a recording of cardiac electrical activity. Previous genome-wide association studies identified genetic variants that modify the QT interval upstream of LITAF (lipopolysaccharide-induced tumor necrosis factor-α factor), a protein encoding a regulator of endosomal trafficking. However, it was not clear how LITAF might impact cardiac excitation. We investigated the effect of LITAF on the voltage-gated sodium channel Nav1.5, which is critical for cardiac depolarization. We show that overexpressed LITAF resulted in a significant increase in the density of Nav1.5-generated voltage-gated sodium current INa and Nav1.5 surface protein levels in rabbit cardiomyocytes and in HEK cells stably expressing Nav1.5. Proximity ligation assays showed co-localization of endogenous LITAF and Nav1.5 in cardiomyocytes, whereas co-immunoprecipitations confirmed they are in the same complex when overexpressed in HEK cells. In vitro data suggest that LITAF interacts with the ubiquitin ligase NEDD4-2, a regulator of Nav1.5. LITAF overexpression down-regulated NEDD4-2 in cardiomyocytes and HEK cells. In HEK cells, LITAF increased ubiquitination and proteasomal degradation of co-expressed NEDD4-2 and significantly blunted the negative effect of NEDD4-2 on INa. We conclude that LITAF controls cardiac excitability by promoting degradation of NEDD4-2, which is essential for removal of surface Nav1.5. LITAF-knockout zebrafish showed increased variation in and a nonsignificant 15% prolongation of action potential duration. Computer simulations using a rabbit-cardiomyocyte model demonstrated that changes in Ca2+ and Na+ homeostasis are responsible for the surprisingly modest action potential duration shortening. These computational data thus corroborate findings from several genome-wide association studies that associated LITAF with QT interval variation.

Business Briefing: Assessing the geopolitical implications of EU AI regulation 17 September 2024 — 4:00PM TO 5:00PM Anonymous (not verified) 8 August 2024 Chatham House

Join us for this critical discussion of how the EU AI Act will shape the world’s approach to the technology.

Join us for this critical discussion of how the EU AI Act will shape the world’s approach to the technology

Governments, technology companies and civil society groups across the world are now advocating firmer AI regulation. Machine learning algorithms have changed the way we interact with technology and powered much of our online lives for decades: why has this pendulum swung back so far toward greater control, and why now?

In 2023 the UK government seized the initiative with its Bletchley AI Safety Summit. The event attempted to address the so called ‘frontier risks’ associated with AI development. Global competition on AI is reflected in AI governance efforts in China, US, the Gulf and beyond. But to date, it is the EU that has led the West in passing AI legislation. The EU AI Act, has separated AI systems into graded risk categories carrying different regulatory requirements, and it remains to be seen whether global AI will feel the Brussels effect.

This conversation will cover the following questions:

• Critics have painted regulation including the AI Act as anti-innovation. Is this a fair assessment?
• What lessons can we learn from the successes and shortcomings of GDPR?
• How do we tackle the challenge of low public trust in AI and low public trust in government technology projects, particularly in Western democracies?
• Does the proliferation of safety institutes, and the AI office, point to the emergence of a new type of technical governance institution? What is its future?

In conversation with David Miliband: Finding a new approach to tackle conflict, climate and extreme poverty 11 September 2024 — 5:00PM TO 5:45PM Anonymous (not verified) 15 August 2024 Chatham House and Online

David Miliband discusses how the climate crisis, extreme poverty and conflict are becoming inextricably linked and how the global community must respond.

Combatting the climate crisis, ending protracted conflicts, and alleviating poverty are three of the greatest priorities for international action. However, these three challenges become increasingly concentrated in a handful of countries. The subsequent feedback loop makes addressing these challenges even more complex.

The International Rescue Committee’s (IRC’s) work in crisis-affected communities highlights this new geography of crisis. Just 16 countries, which are both climate-vulnerable and conflict-affected. This represents 43% of all people living in extreme poverty, 44% of all people affected by natural disasters and 79% of all people in humanitarian need. This trend towards the concentration of crisis is only deepening. In three decades, the number of conflict-affected, climate-vulnerable states has increased from 44% to more than two-thirds.

Affected countries - like Sudan, Myanmar, and Syria - are also among the least supported financially. Debt burdens are siphoning away critical resources needed for adaptation and resilience. Humanitarian aid budgets are being slashed by donor governments. The private sector refuses to invest in these communities they view as too risky. And the international financial institutions meant to alleviate poverty and spur climate action are not well-designed to work with crisis-affected states or local communities. With the upcoming COP29 Summit in Azerbaijan focused on the New Collective Quantified Goal for climate finance, vulnerable communities will be watching closely whether they will get support in their fight against the worst impacts of the climate crisis.

Conflict, the climate crisis, and extreme poverty are taking their toll. But how can the world best respond?

Key questions to be discussed during the session include:

• At a time of political disruption, how does the West engage with vulnerable countries? What actions should be prioritised in providing support to such countries?
• Can global institutions evolve to better protect vulnerable and displaced people from conflict and climate-risk, particularly as geopolitical rivalries reduce space for cooperation?
• What is the UK’s role in supporting climate action in fragile states and how does this align with its agenda on the Sustainable Development Goals and extreme poverty?

Islamic radicalisation in Central Asia 18 September 2024 — 10:00AM TO 11:30AM Anonymous (not verified) 20 August 2024 Chatham House and Online

Experts analyse rising foreign recruitment, current counter-radicalisation efforts and challenge past Chatham House predictions made of the Central Asia region.

In 2014, Chatham House released a report titled The Myth of Post-Soviet Muslim Radicalisation in the Central Asian Republics. At that time, a significant, Western-funded counter-radicalisation industry was addressing what was believed to be a major issue of Islamic violent extremism in the region.

Over the past decade, two key developments have occurred. First, Western interest in the region has declined in favour of traditional geopolitical concerns. Second, while violent extremism incidents within Central Asia remain rare, there has been a notable recruitment of Central Asians by foreign groups, with several attacks carried out by Central Asians overseas.

In this event, the original report’s authors, John Heathershaw and David Montgomery, will discuss whether the report’s arguments are still valid and how we might answer these questions today.

This raises several questions:

• What did the report accurately predict, and where did it fall short?
• How can we explain the lack of violent extremist organisations (VEOs) within Central Asia but the presence of Central Asians in VEOs abroad?
• Could repression by Central Asian states both domestically and transnationally have contributed to this issue?
• What, if anything, can the counter-radicalisation industry do today to address this problem more effectively?

Please note that in-person places are limited. Please wait for confirmation before participating. 

Director’s Briefing: Assessing foreign policy challenges for the next US president 5 September 2024 — 2:00PM TO 3:00PM Anonymous (not verified) 27 August 2024 Chatham House and Online

This briefing will explore what challenges might await the winner of 2024 US presidential election.

As the 2024 US Presidential election draws closer, the future direction of American foreign policy seems ever more uncertain. Kamala Harris, the Democratic presidential candidate, appears to be embracing many of Biden’s policies, but she brings a different background, and most likely a different team, so change is likely.  Donald Trump has more well-known views on foreign policy, but the context for a second Trump administration would be very different than the first.

The next U.S. President will be confronted a world in need of leadership with two major wars, a more assertive and capable China, a climate crisis, ungoverned technological change, emerging powers that demand a seat at the table, and debt distress across much of the developing world.

Please join us for this critical conversation covering:

• How will US-China strategic competition and the threat of conflict over Taiwan challenge US policy makers?
• What are the risks and challenges posed by Russia’s illegal full-scale invasion of Ukraine?
• How does war in the Middle East and the threat of regional escalation shape US foreign policy?

How can young people in MENA thrive despite economic and political insecurity? 24 September 2024 — 2:00PM TO 3:00PM Anonymous (not verified) 30 August 2024 Online

Experts share insights on how young people navigate challenges and find opportunities in a changing domestic and regional landscape.

Across the Middle East and North Africa young people between the ages of 15 and 29 comprise around 24 per cent of the population in the region. As the complex regional geopolitical developments unfold, the majority of these young people are living in a time of economic and political insecurity, with many, such as Iraqis and Libyans, also growing up during conflict and uncertainty.

Enhanced education and employment programs are key opportunities for development and stability in the region. Despite this, limited resources and competing priorities have meant that governments often struggle to deliver competitive educational and employment opportunities and lack the capacity and funding for education reform and active labour market policy development. Key tensions that pit modernity and autonomy against tradition and control continue to frame the education and skills development landscape.

This webinar will address:

• The challenges young people within the MENA region face in different contexts;
• The role education and employment play in developing skills for 21st century challenges;
• Spaces for young people to practice citizenship and participate in political processes;
• Youth’s economic prospects while navigating the tumultuous backdrop of enduring conflict and authoritarianism. 

Fostering inclusive health systems amidst geopolitical instability 13 October 2024 — 9:00AM TO 10:00AM Anonymous (not verified) 11 September 2024 Sheraton Berlin Grand Hotel Esplanade

How can we build trust and inclusivity in the health sector in a fractured geopolitical environment?

Building trust in government, service provision and delivery are crucial considerations for policymakers who aim to make local, national and international health systems more inclusive. In the health space, trust can be a matter of life and death. Understanding and modulating policies that account for the trust factor, alongside the geopolitical determinants of health, can lead to more inclusive decision making and thus better health outcomes for larger proportions of a population.

International unity is key to addressing the challenges posed by geopolitical instability, which include disinformation campaigns, rising nationalism and growing divisions between states. If countries can find common ground through an inclusive approach to health, the effects could be transformative in achieving global health and equity targets.

This discussion, held in partnership with Haleon, will examine what it takes to foster trust and resilience in the health sector, achieve global inclusivity aims and chart a path for the public and private spheres to come together to navigate a fractured geopolitical environment.

• In what ways can localised health inclusivity data help policymakers to alleviate gaps in healthcare provision and why is this an essential element in instilling trust across the system?
• What role should multilateral organizations play in setting precedents for health inclusivity around the world?
• How do health inclusivity policies empower the service user and help reduce the burden placed on public healthcare systems?
• How can the health sector come together to ensure individuals are included within their own health decisions, are able to access services regardless of demographics and geography and trust their healthcare providers?

This event will be held at the Sheraton Hotel, Grand Esplanade, Berlin in the margins of the World Health Summit. You do not need a ticket for the World Health Summit to attend this event.

In conversation with Martin Griffiths: How can a divided world address conflict? 1 October 2024 — 10:00AM TO 11:00AM Anonymous (not verified) 16 September 2024 Chatham House and Online

The former United Nations Under-Secretary-General describes how a weakening multilateralism system and dysfunctional political diplomacy can be revitalized by a humanitarian approach.

US domestic polarization and implications for the presidential election 30 September 2024 — 5:00PM TO 6:00PM Anonymous (not verified) 19 September 2024 Online

This webinar explores the rise of polarization amongst the US public and implications for the upcoming election.

Domestic polarization has been on the rise in the US in recent years, with Democrats and Republicans moving further away from the centre on key policy issues. As polarization increases, so too do concerns about the state of US democracy and prospects of political violence surrounding the upcoming presidential election. 

This expert panel discusses key questions including:

• What are the driving forces of the growing political divide in the US?
• How far apart are voters on key election issues, from healthcare to immigration to national security?
• How is partisan polarisation altering the effectiveness of US foreign policy and influencing America’s role in the world?

Business Briefing: US election geopolitical and economic risk scenarios 10 October 2024 — 11:45AM TO 1:00PM Anonymous (not verified) 23 September 2024 Chatham House

Please join us for this critical discussion of the US Election related global business risks.

The outcome of the US presidential election will have significant, intersecting implications for global as well as American business. At stake will be the degree of continuity and stability on both the domestic and international fronts, with a Harris presidency pursuing policies building broadly on the Biden Administration and a second Trump Administration departing sharply from them—with both shaped and limited by control of Congress.

An already volatile geopolitical environment and global economy may become even more unpredictable in the face of potential American political instability and uncertain leadership in the international community.

Please join us for this critical session to discuss:

• How might trade policy differ between a Harris and Trump presidency? Will national security pressures, especially over China, lead to greater policy commonalities than expected?

• What might differing approaches to decarbonization and the energy transition mean for the future of policy toward EVs, critical mineral supply chains, and ‘green’ industrial subsidy?

• How might each Administration approach fiscal policy? Will either push for a tightening to the current loose policy—and what may be implications for US debt and the dollar?

• What economic effects can we expect in the case of a disputed election result or non-peaceful transfer of power—and will Corporate America be compelled to make public statements?

Shaping modern Britain: the role of African and Caribbean communities 24 October 2024 — 5:00PM TO 6:00PM Anonymous (not verified) 3 October 2024 Chatham House and Online

As part of Black History Month, this event celebrates the enduring contributions of African and Caribbean communities to the UK.

When British colonial rule ended, newly independent countries in Africa and the Caribbean retained influences such as the English language and governance systems modelled on that of the UK. Initially, these post-independence relations were largely marked by the UK’s soft power, shaping the nation-building processes in these regions.

Over time, however, this influence has become a two-way exchange. African and Caribbean cultures have profoundly shaped modern Britain – from music and food to sports, arts, literature and beyond. These evolving dynamics have not only enriched the UK’s cultural landscape but also provided significant benefits for diaspora communities, fostering a sense of belonging and promoting cultural exchange. Diaspora groups and civil society organizations have adeptly utilised these connections to advocate for their communities and advance their interests.

At this event, speakers will explore how African and Caribbean influences rose to prominence in the UK and how this cultural momentum can be harnessed to build stronger, forward-looking partnerships. By highlighting the shared histories and more vibrant present-day exchanges, this event will explore how these ties can be used to break down stereotypes, promote social cohesion, and contribute to a more inclusive future.

This event forms part of our series of events celebrating Black History Month, including a photo exhibition and drinks reception.

Is the world ready for the next pandemic? 29 October 2024 — 6:00PM TO 7:00PM Anonymous (not verified) 9 October 2024 Chatham House and Online

In a joint event with The Elders, Helen Clark, Ban Ki-moon and other experts discuss the policies needed to prevent the next health catastrophe. A drinks reception will follow this event.

The world faces multiple interlinked existential threats such as pandemics and the climate crisis, exacerbated by conflict and extreme poverty. However, the multilateral system is failing to respond with sufficient urgency or impact. As the fifth anniversary of the COVID-19 pandemic approaches, Chatham House and The Elders will discuss the risk of a general slide into complacency. 

Amid the expanding outbreak of mpox in Africa, rich countries continue to withhold stockpiled mpox vaccines. The failure to release the required amount is contributing to the diseases spread across the continent. 

Meanwhile, the Pandemic Accord negotiations are in overtime, with nations unable to reach agreement over concerns around sovereignty and resource distribution in any future pandemic. Similarly, a proposal to include a UN Emergency Platform in the recent Summit of the Future to strengthen the multilateral response to complex global shocks was shelved due to political deadlock.

Can the world learn from past mistakes and break the cycle of panic and neglect? In today’s fractious and polarized geopolitical context, what would it take for leaders to do what’s necessary? And why is it so critical to have equity at the heart of any sustainable global response?

Join Chatham House for this event in which the panel discuss key questions including:

• Five years on from COVID-19, who is showing global leadership today in preparing for future pandemics?
• Are international organizations and institutions fit for purpose to respond to pandemics in a multipolar geopolitical environment? How can they best adapt?
• What can be done to clarify and detoxify current debates around sovereignty to improve global pandemic prevention, preparedness and response?

Numerous iron-sulfur (Fe-S) proteins with diverse functions are present in the matrix and respiratory chain complexes of mitochondria. Although [4Fe-4S] clusters are the most common type of Fe-S cluster in mitochondria, the molecular mechanism of [4Fe-4S] cluster assembly and insertion into target proteins by the mitochondrial iron-sulfur cluster (ISC) maturation system is not well-understood. Here we report a detailed characterization of two late-acting Fe-S cluster-carrier proteins from Arabidopsis thaliana, NFU4 and NFU5. Yeast two-hybrid and bimolecular fluorescence complementation studies demonstrated interaction of both the NFU4 and NFU5 proteins with the ISCA class of Fe-S carrier proteins. Recombinant NFU4 and NFU5 were purified as apo-proteins after expression in Escherichia coli. In vitro Fe-S cluster reconstitution led to the insertion of one [4Fe-4S]2+ cluster per homodimer as determined by UV-visible absorption/CD, resonance Raman and EPR spectroscopy, and analytical studies. Cluster transfer reactions, monitored by UV-visible absorption and CD spectroscopy, showed that a [4Fe-4S]2+ cluster-bound ISCA1a/2 heterodimer is effective in transferring [4Fe-4S]2+ clusters to both NFU4 and NFU5 with negligible back reaction. In addition, [4Fe-4S]2+ cluster-bound ISCA1a/2, NFU4, and NFU5 were all found to be effective [4Fe-4S]2+ cluster donors for maturation of the mitochondrial apo-aconitase 2 as assessed by enzyme activity measurements. The results demonstrate rapid, unidirectional, and quantitative [4Fe-4S]2+ cluster transfer from ISCA1a/2 to NFU4 or NFU5 that further delineates their respective positions in the plant ISC machinery and their contributions to the maturation of client [4Fe-4S] cluster-containing proteins.

The human cardiovascular system has adapted to function optimally in Earth's 1G gravity, and microgravity conditions cause myocardial abnormalities, including atrophy and dysfunction. However, the underlying mechanisms linking microgravity and cardiac anomalies are incompletely understood. In this study, we investigated whether and how calpain activation promotes myocardial abnormalities under simulated microgravity conditions. Simulated microgravity was induced by tail suspension in mice with cardiomyocyte-specific deletion of Capns1, which disrupts activity and stability of calpain-1 and calpain-2, and their WT littermates. Tail suspension time-dependently reduced cardiomyocyte size, heart weight, and myocardial function in WT mice, and these changes were accompanied by calpain activation, NADPH oxidase activation, and oxidative stress in heart tissues. The effects of tail suspension were attenuated by deletion of Capns1. Notably, the protective effects of Capns1 deletion were associated with the prevention of phosphorylation of Ser-345 on p47phox and attenuation of ERK1/2 and p38 activation in hearts of tail-suspended mice. Using a rotary cell culture system, we simulated microgravity in cultured neonatal mouse cardiomyocytes and observed decreased total protein/DNA ratio and induced calpain activation, phosphorylation of Ser-345 on p47phox, and activation of ERK1/2 and p38, all of which were prevented by calpain inhibitor-III. Furthermore, inhibition of ERK1/2 or p38 attenuated phosphorylation of Ser-345 on p47phox in cardiomyocytes under simulated microgravity. This study demonstrates for the first time that calpain promotes NADPH oxidase activation and myocardial abnormalities under microgravity by facilitating p47phox phosphorylation via ERK1/2 and p38 pathways. Thus, calpain inhibition may be an effective therapeutic approach to reduce microgravity-induced myocardial abnormalities.

The cystic fibrosis transmembrane conductance regulator (CFTR) is a plasma membrane anion channel that plays a key role in controlling transepithelial fluid movement. Excessive activation results in intestinal fluid loss during secretory diarrheas, whereas CFTR mutations underlie cystic fibrosis (CF). Anion permeability depends both on how well CFTR channels work (permeation/gating) and on how many are present at the membrane. Recently, treatments with two drug classes targeting CFTR—one boosting ion-channel function (potentiators) and the other increasing plasma membrane density (correctors)—have provided significant health benefits to CF patients. Here, we present an image-based fluorescence assay that can rapidly and simultaneously estimate both CFTR ion-channel function and the protein's proximity to the membrane. We monitor F508del-CFTR, the most common CF-causing variant, and confirm rescue by low temperature, CFTR-targeting drugs and second-site revertant mutation R1070W. In addition, we characterize a panel of 62 CF-causing mutations. Our measurements correlate well with published data (electrophysiology and biochemistry), further confirming validity of the assay. Finally, we profile effects of acute treatment with approved potentiator drug VX-770 on the rare-mutation panel. Mapping the potentiation profile on CFTR structures raises mechanistic hypotheses on drug action, suggesting that VX-770 might allow an open-channel conformation with an alternative arrangement of domain interfaces. The assay is a valuable tool for investigation of CFTR molecular mechanisms, allowing accurate inferences on gating/permeation. In addition, by providing a two-dimensional characterization of the CFTR protein, it could better inform development of single-drug and precision therapies addressing the root cause of CF disease.

The main protease (3CL Mpro) from SARS–CoV-2, the etiological agent of COVID-19, is an essential enzyme for viral replication. 3CL Mpro possesses an unusual catalytic dyad composed of Cys145 and His41 residues. A critical question in the field has been what the protonation states of the ionizable residues in the substrate-binding active-site cavity are; resolving this point would help understand the catalytic details of the enzyme and inform rational drug development against this pernicious virus. Here, we present the room-temperature neutron structure of 3CL Mpro, which allowed direct determination of hydrogen atom positions and, hence, protonation states in the protease. We observe that the catalytic site natively adopts a zwitterionic reactive form in which Cys145 is in the negatively charged thiolate state and His41 is doubly protonated and positively charged, instead of the neutral unreactive state usually envisaged. The neutron structure also identified the protonation states, and thus electrical charges, of all other amino acid residues and revealed intricate hydrogen-bonding networks in the active-site cavity and at the dimer interface. The fine atomic details present in this structure were made possible by the unique scattering properties of the neutron, which is an ideal probe for locating hydrogen positions and experimentally determining protonation states at near-physiological temperature. Our observations provide critical information for structure-assisted and computational drug design, allowing precise tailoring of inhibitors to the enzyme's electrostatic environment.

In their comment (1) on our publication (2), the authors make two points: (i) they raise concerns about the possible effect of residual NONOate in our study, and (ii) they promote nitrosylcobalamin (NOCbl) supplied by their own company. Both points lack merit for the following reasons. The authors make the astonishing claim that the spectra of nitric oxide (NO•) and cobalamins overlap. Unlike NO•, cobalamin absorbs in the visible region, permitting unequivocal spectral assignment of NOCbl as reported (3). We demonstrated that whereas NOCbl is highly unstable in solution, it is stabilized by the B12 trafficking protein CblC. So even if present, residual NONOate (which is unstable at neutral pH and is removed during the work-up (3)) could not account for the observed difference.The authors then misrepresent our synthetic method, claiming that anaerobic conditions were used to generate nitrocobalamin (NO2Cbl), which results in the transient formation of NOCbl. We synthesized NO2Cbl aerobically using nitrite as described (4); NOCbl is not an intermediate in this ligand exchange reaction. The aerobic instability of NOCbl has been rigorously described by inorganic chemists (3, 5) and raises obvious questions about its purported biological effects as exemplified by the authors' own 2003 JBC publication, which was later withdrawn.As to promoting NOCbl from their company, the authors refer to a synthetic route from a mixture of NO• gas and aquocobalamin. The authors' method (6) has been described as “dubious” by chemists (5). Whereas DEAE NONOate used in our method is widely known as an NO• donor,...